Triterpene derivatives and pharmaceuticals for treating hepatic disorders

ABSTRACT

A pharmaceutical composition for treating a hepatic disorder, comprising a triterpene derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof is disclosed:                    
     wherein 
     R 1  represents a hydroxyl group, alkoxy, alkylcarbonyloxy, or aralkyloxy; R 2  represents alkyl, —CH 2 OR 5 , wherein R 5  represents a hydrogen atom, alkyl, aralkyl, or alkylcarbonyl, formyl, —COOR 6 , wherein R 6  represents a hydrogen atom or alkyl, or —CH 2 N(R 7 )R 8 ; or R 1  and R 2  combine with each other to form —O—CR 9 (R 10 )—OCH 2 —, wherein R 9  and R 10 , which may be the same or different, represent a hydrogen atom, alkyl, or aryl; R 3  and R 4 , which may be the same or different, represent a hydrogen atom, a hydroxyl group, alkyl, hydroxyalkyl, formyl, —COOR 11 , wherein R 11  represents a hydrogen atom or alkyl, or —OR 12 , wherein R 12  represents alkyl, aralkyl, C 1-6  alkylcarbonyl, arylcarbonyl, alkenyl, alkenylcarbonyl, or arylalkenylcarbonyl which may be optionally substituted; or R 3  and R 4  combine with each other to form a methylene group; and  — — —  represents a single or double bond, provided that, when  — — —  represents a double bond, R 4  is absent.

BACKGROUND OF THE INVENTION

1. Field of Invention

The present invention relates to triterpene derivatives usable astherapeutic agents for hepatic disorders.

2. Description of the Related Art

A liver is an important organ which has various functions necessary formaintaining life of a living body, such as detoxication, variousmetabolisms, and storage of substances. It, however, often undergoesacute or chronic damage due to viruses, drugs, alcohols and othervarious causes. This induces viral hepatitis, drug-induced hepatopathy,alcoholic hepatopathy, fatty liver, and, in addition, diseases such ascirrhosis and hepatic cancer.

For treating such disorders, alimentary therapy, rest cure, and othertherapies using glycyrrhizin preparations, adrenocortical steroids,interferons and the like have hitherto been employed. These therapies,however, may not be satisfactorily effective for the treatment of thehepatic disorders. Glycyrrhizin and interferon are intravenouslyadministered and, hence, unsuitable for prolonged administration.Further, the interferon and steroids have a problem of side effect.

Some triterpene derivatives have anticomplementary activity and plateletaggregation inhibitory activity. Thus, they are known as prophylacticand therapeutic agents for immunological diseases and thrombosis(Japanese Patent Laid-Open No. 85344/1986). Further, triterpenederivatives are disclosed, for example, in Japanese Patent Laid-Open No.37749/1986, Chem. Pharm. Bull., 36, 153 (1988), Chem. Pharm. Bull., 24,121 (1976), Chem. Pharm. Bull., 30, 2294 (1982), Chem. Pharm. Bull., 33,4267 (1985), Chem. Pharm. Bull., 31, 664 (1983), Chem. Pharm. Bull., 31,674 (1983), Phytochemistry 27, 3563 (1988), Planta Medica 46, 52 (1982),J. Chem. Soc., and Chem. Comm., 785 (1982).

However, so far as the present inventors know, there is no report whichdiscloses that the triterpene derivatives are effective as a therapeuticagent for treating hepatic disorders.

SUMMARY OF THE INVENTION

The present inventors have now found that triterpene derivatives areeffective for treating hepatic disorders. Further, they have succeededin synthesis of novel triterpene derivatives. The present invention isbased on such novel finding.

Thus, according to one aspect of the present invention, there isprovided a therapeutic agent for a hepatic disorder, comprising atriterpene derivative represented by the formula (I) or apharmaceutically acceptable salt thereof:

wherein

R¹ represents a hydroxyl group,

C₁₋₆ alkoxy,

C₁₋₆ alkylcarbonyloxy, or aralkyloxy which may be optionallysubstituted;

R² represents C₁₋₆ alkyl,

—CH₂OR⁵ wherein R⁵ represents a hydrogen atom, C₁₋₆ alkyl, aralkyl whichmay be optionally substituted, or C₁₋₆ alkylcarbonyl,

formyl,

—COOR⁶ wherein R⁶ represents a hydrogen atom or C₁₋₆ alkyl), or

—CH₂N(R⁷)R⁸ wherein R⁷ and R⁸, which may be the same or different,represent a hydrogen atom or C₁₋₆ alkyl; or

R¹ and R² may combine with each other to form —O—CR⁹(R¹⁰)—OCH₂— whereinR⁹ and R¹⁰, which may be the same or different, represent a hydrogenatom, C₁₋₆ alkyl, or aryl;

R³ and R⁴, which may be the same or different, represent

a hydrogen atom,

a hydroxyl group,

C₁₋₆ alkyl,

hydroxy C₁₋₆ alkyl,

formyl,

—COOR¹¹ wherein R¹¹ represents a hydrogen atom or C₁₋₆ alkyl, or

—OR¹² wherein R¹² represents C₁₋₆ alkyl, aralkyl which may be optionallysubstituted, C₁₋₆ alkylcarbonyl, arylcarbonyl which may be optionallysubstituted, C₂₋₆ alkenyl, C₂₋₆ alkenylcarbonyl, or arylalkenylcarbonylwhich may be optionally substituted; or

R³ and R⁴ combine with each other to form a methylene group;

— — — represents a single or double bond, provided that, when — — —represents a double bond, R⁴ is absent.

The novel triterpene derivative according to another aspect of thepresent invention is represented by the formula (II) or apharmaceutically acceptable salt thereof:

wherein

R¹ represents a hydroxyl group,

C₁₋₆ alkoxy,

C₁₋₆ alkylcarbonyloxy, or

aralkyloxy which may be optionally substituted;

R² represents C₁₋₆ alkyl,

—CH₂OR⁵ wherein R⁵ represents a hydrogen atom, C₁₋₆ alkyl, aralkyl whichmay be optionally substituted, or C₁₋₆ alkylcarbonyl,

formyl,

—COOR⁶ wherein R⁶ represents a hydrogen atom or C₁₋₆ alkyl), or

—CH₂N(R⁷)R⁸ wherein R⁷ and R⁸, which may be the same or different,represent a hydrogen atom or C₁₋₆ alkyl; or

R¹ and R² may combine with each other to form —O—CR⁹(R¹⁰)—OCH₂— whereinR⁹ and R¹⁰, which may be the same or different, represent a hydrogenatom, a C₁₋₆ alkyl group, or aryl which may be optionally substituted;

R³ and R⁴, which may be the same or different, represent

C₁₋₆ alkyl,

hydroxy C₁₋₆ alkyl,

formyl,

—COOR¹¹ wherein R¹¹ represents a hydrogen atom or C₁₋₆ alkyl, or

—OR¹² wherein R¹² represents C₁₋₆ alkyl, aralkyl which may be optionallysubstituted, arylcarbonyl which may be optionally substituted, C₂₋₆alkenyl, C₂₋₆ alkenylcarbonyl, or arylalkenylcarbonyl which may beoptionally substituted; or

R³ and R⁴ may combine with each other to form a methylene group;

— — — represents a single or double bond, provided that, when — — —represents a double bond, R⁴ is absent;

when R¹ and R² may combine with each other to form -—O—CR⁹(R¹⁰)—OCH₂—wherein any one of R⁹ and R¹⁰ represents aryl, R³ and R⁴ may furtherrepresent a hydrogen atom, a hydroxyl group, or aralkyloxy;

when any one of R³ and R⁴ represents a C₁₋₆ alkyl group, the other mayfurther represent a hydroxyl group; and

when R² represents —CH₂OR⁵, R³ and R⁴ may further represent a hydrogenatom.

Further, novel compounds provided by the present invention are:

a compound represented by the formula (II) wherein R¹ represents ahydroxyl group, R² represents —COOO—C₁₋₆alkyl, R³ represents a hydrogenatom and R⁴ represents a hydroxyl group;

a compound represented by the formula (II) wherein R¹ represents C₁₋₆alkoxy, R² represents —CH₂OH, R³ represents a hydrogen atom and R⁴represents a hydroxyl group,

a compound represented by the formula (II) wherein R¹ representsaralkyloxy, R² represents formyl, carboxyl, —COO—C₁₋₆ alkyl, or —CH₂OR⁵,wherein R⁵ represents a hydrogen atom, C₁₋₆ alkyl, or C₁₋₆alkylcarbonyl, R³ represents a hydrogen atom and R⁴ representsaralkyloxy which may be optionally substituted; and

a compound represented by the formula (II) wherein R¹ represents ahydroxyl group or C₁₋₆ alkoxy, R² represents aralkyloxymethyl which maybe optionally substituted, R³ represents a hydrogen atom and R⁴represents aralkyloxy which may be optionally substituted.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Therapeutic Agent for Hepatic Disorders/Compounds of Formula (I)

The compounds represented by the formula (I) and salts thereof areeffective for the treatment of hepatic disorders. Hepatic disorders, towhich the compounds represented by the formula (I) can be applied,include acute and chronic viral hepatitis, and drug-induced, toxic,alcoholic, intrahepatic cholestasis, and inborn metabolic errorhepatopathy. The term “hepatopathy” used herein refers to inflammatorydiseases and, depending upon the progress of symptom, is used as a terminclude also fatty liver, cirrhosis, and hepatoma.

Specifically, the triterpene derivatives represented by the formula (I),when incubated together with human hepatoma cells (Hep G2) in thepresence of aflatoxin B₁ (hepatopathy-inducing substance), has aninhibitory activity against necrosis of such cells.

As used herein, the term “alkyl” as a group or a part of a group meansboth straight and branched chain alkyls.

Specific examples of this group include methyl, ethyl, propyl,iso-propyl, n-butyl, iso-butyl, and t-butyl. The term “halogen atom”means a fluorine, chlorine, bromine, or iodine atom. The term “aryl” asa group or a part of a group preferably means phenyl, naphthyl, tolyl,methoxyphenyl or the like. The term “aralkyl” as a group or a part of agroup preferably means phenyl C₁₋₄ alkyl, more preferably benzyl,phenethyl or the like. One or more hydrogen atoms, preferably one or twohydrogen atoms, on the “aryl” or “aralkyl” may be optionallysubstituted, and examples of the substituent include a hydroxyl group,C₁₋₆ alkoxy (preferably C₁₋₄ alkoxy, more preferably methoxy), a halogenatom, amino, dimethylamino, acetoxy, methylenedioxy, and nitro. Examplesof substituted aryl and aralkyl include methoxy, phenyl, hydroxyphenyl,dihydroxyphenyl, and dimethoxyphenyl.

In the formula (I), the C₁₋₆ alkoxy represented by R¹ is preferably C₁₋₄alkoxy, more preferably methoxy or ethoxy. Specific examples thereofinclude methoxy, ethoxy, propyloxy, butyloxy, pentyloxy, and hexyloxy.The C₁₋₆ alkylcarbonyl is preferably C₁₋₄ alkylcarbonyl, and specificexamples thereof include acetyl, propionyl, butyryl, pentanoyl, andhexanoyl. The aralkyloxy represented by R¹ is preferably benzyloxy,phenetyloxy, methylbenzyloxy, and naphthylmethyloxy.

In the formula (I), —CH₂OR⁵ represented by R² is preferably —CH₂OH, —CHO—C₁₋₄ alkyl, —CH₂O— (phenyl C₁₋₄ alkyl), or —CH₂O—CO—C₁₋₄ alkyl, morepreferably hydroxymethyl. The group —COOR⁶ represented by R² ispreferably —COO—C₁₋₆ alkyl or COOH.

Further, in the formula (I), R¹ and R² may combine with each other toform —O—CR⁹(R¹⁰)—OCH₂— wherein R⁹ and R¹⁰, which may be the same ordifferent, represent a hydrogen atom, C₁₋₆ alkyl, or aryl. Preferredexamples thereof include —O—CR⁹(R¹⁰)—OCH₂— wherein both R⁹ and R¹⁰represent C₁₋₆ alkyl, preferably C₁₋₄ alkyl, more preferably methyl orethyl and —O—CR⁹(R¹⁰)—OCH₂— wherein any one of R⁹ and R¹⁰ represent ahydrogen atom with the other representing aryl, preferably phenyl,tolyl, xylyl, biphenyl, naphthyl, anthryl, or phenanthryl.

In the formula (I), the C₁₋₆ alkyl represented by R³ R⁴ is preferablyC₁₋₄ alkyl, more preferably methyl or ethyl. The hydroxy C₁₋₆ alkylrepresented by R³ and R⁴ is preferably hydroxy C₁₋₄ alkyl, morepreferably hydroxymethyl.

In the formula (I), —COOR¹¹ represented by R³ or R⁴ is preferably —COOHor —COO—C₁₋₄ alkyl.

Further, in the formula (I), R¹² in —OR¹² represented by R³ or R⁴represents C₁₋₆ alkyl, aralkyl, C₁₋₆ alkylcarbonyl, arylcarbonyl, C₂₋₆alkenyl, C₂₋₆ alkenylcarbonyl, or arylalkenylcarbonyl. Further, the C₂₋₆alkenyl is preferably C₂₋₄ alkenyl, and specific examples thereofinclude vinyl, propenyl, allyl, butenyl, 2-methylpropenyl, pentenyl, andhexenyl. Examples of the aralkyl include benzyl, phenethyl,methylbenzyl, naphthylmethyl, and phenylpropyl. The C₁₋₆ alkylcarbonylis preferably C₁₋₄ alkylcarbonyl, and specific examples thereof includeacetyl, propionyl, butyryl, pentanoyl, and hexanoyl. Preferred examplesof arylcarbonyls include benzoyl and naphthylcarbonyl. The C₂₋₆ alkenylis preferably C₂₋₄ alkenylcarbonyl, and specific examples thereofinclude acryloyl, allylcarbonyl, and butenoyl. The C₂₋₆ alkenylcarbonylis preferably C₂₋₄ alkenylcarbonyl. Specific examples of thearylalkenylcarbonyl include cinnamoyl and phenylbutenoyl.

R³ and R⁴ may combine with each other to form a methylene group.

In the formula (I), — — — represents a single bond or a double bond.

When — — — represents a double bond, preferably, R¹ represents ahydrogen atom with R² representing —CH₂OH, or R¹ and R² combine witheach other to form —O—CR⁹(R¹⁰)—OCH₂—, wherein R⁹ and R¹⁰ are as definedabove, and R³ represents a hydrogen atom.

The compounds represented by the formula (I) have isomers, and thepresent invention embraces such isomers and mixtures thereof.

According to a preferred embodiment of the present invention, preferredcompounds have a configuration represented by the following formula(I-1):

Further, the compounds represented by the formula (I) can easily form asalt with a pharmaceutically acceptable base. Preferred bases includeinorganic bases, such as sodium hydroxide, potassium hydroxide, aluminumhydroxide, sodium carbonate, potassium carbonate, and sodiumhydrogencarbonate, and organic bases, such as piperazine, morpholine,piperidine, ethylamine, and trimethylamine.

Preferred compounds, of the present invention, represented by theformula (I) include:

a group of compounds wherein R¹ represents a hydroxyl group, R²represents —CH₂OR⁵ and R³ represents a hydrogen atom, amoung them, morepreferably a group of compounds wherein R⁴ represents a hydroxyl groupor —OR¹² and a group of compounds wherein R¹ represents C₁₋₆ alkoxy,

a group of compounds wherein R¹ represents a hydroxyl group, R²represents formyl, R³ represents a hydrogen atom and R⁴ represents ahydroxyl group,

a group of compounds wherein R¹ represents a hydroxyl group oraralkyloxy, R² represents —COOR⁶, R³ represents a hydrogen atom and R⁴represents a hydroxyl group or —OR¹²,

a group of compounds wherein R¹ represents a hydroxyl group, C₁₋₆alkoxy, or C₁₋₆ alkylcarbonyloxy, R² represents —CH₂OR⁵, and R³ and R⁴represent a hydrogen atom,

a group of compounds wherein R¹ represents a hydroxyl group, R²represents —CH₂OR⁵, R³ represents C₁₋₆ alkyl, and R⁴ represents ahydroxyl group, and

a group of compounds wherein R¹ represents a hydroxyl group, R²represents —CH₂OR⁵, R³ represents a hydrogen atom and R⁴ representshydroxy C₁₋₆ alkyl or carboxyl.

Although the compound represented by the formula (I) may be administeredas a raw material, it may be preferably administered as a pharmaceuticalcomposition. A pharmaceutical composition, as a therapeutic agent forhepatic disorders, comprising as an active ingredient the compound ofthe formula (I) or a salt thereof can be administered either orally orparenterally (e.g., intravenous injection, intramuscular injection,subcutaneous administration, rectal administration, percutaneousadministration) to humans or animals other than humans.

Therefore, the therapeutic agent for hepatic disorders according to thepresent invention may be made into a formulation suitable for the routeof administration. Specifically, it may be made into any of thefollowing preparations: an injection such as intravenous orintramuscular injection; an oral preparation such as a capsule, atablet, a granule, a powder, a pill, fine subtilaes, or a troche; apreparation for rectal administration; an oleaginous suppository; and anaqueous suppository. The above-described various preparations can beprepared by a conventional method using an excipient, a filler, abinder, a wetting agent, a disintegrating agent, a surface active agent,a lubricant, a dispersing agent, a buffer, a preservative, asolubilizer, an antiseptic, a flavor, a soothing agent, a stabilizer andthe like. Examples of the above additives which are nontoxic andemployable in the preparations include milk sugar, fruit sugar, grapesugar, starch, gelatin, magnesium carbonate, synthetic magnesiumsilicate, talc, magnesium stearate, methyl cellulose, carboxymethylcellulose or a salt thereof, gum arabic, polyethylene glycol, syrup,vaseline, glycerin, ethanol, propylene glycol, citric acid, sodiumchloride, sodium sulfite and sodium phosphate.

The dosage of the compound represented by the formula (I) may varydepending upon the age, weight, conditions, or severity of the diseaseof a patient. In general, however, it is approximately 0.1 to 1000 mg,preferably 1 to 100 mg per day for adult human, once or twice a day. Theadministration may be made either orally or parenterally.

Novel triterpene derivatives/compounds of formula (II)

According to another aspect of the present invention, novel triterpenederivatives are provided. The novel triterpene derivatives of thepresent invention are compounds represented by the formula (II).

In the formula (II), when R¹, R², R³, and R⁴ are as defined above in theformula (I), preferred compounds represented by the formula (II) may bethe same as those described above in the formula (I).

The compounds represented by the formula (II) also have isomers, and thepresent invention embraces these isomers and mixtures thereof.

According to a preferred embodiment of the present invention, preferredcompounds have a configuration represented by the following formula(II-1):

Further, the compounds represented by the formula (II) can easily form asalt with a pharmaceutically acceptable base. Preferred bases includethose exemplified above in the formula (I).

According to a preferred embodiment of the present invention, preferredcompounds, of the present invention, represented by the formula (II)include:

a group of compounds wherein R¹ represents a hydroxyl group, R²represents —CH₂OR⁵ and R³ represents a hydrogen atom, particularly agroup of compounds wherein R⁵ represents a hydrogen atom and R⁴represents —OR¹² wherein R¹² represents C₁₋₆ alkyl, aralkyl,arylcarbonyl, C₂₋₆ alkenyl, C₂₋₆ alkenylcarbonyl, orarylalkenylcarbonyl,

a group of compounds wherein R¹ and R² combine with each other to form—O—CR⁹(R¹⁰)—OCH₂, particularly a group of compounds wherein R⁹ and R¹⁰represent methyl, R³ represents a hydrogen atom and R⁴ represents —OR¹²wherein R¹² represents C₁₋₆ alkyl, aralkyl, arylcarbonyl, C₂₋₆ alkenyl,C₂₋₆ alkenylcarbonyl, or arylalkenylcarbonyl, a group of compoundswherein R⁹ represents a hydrogen atom and R¹⁰ represents aryl, and agroup of compounds wherein R³ and R⁴ represent a hydrogen atom, or R³represents a hydrogen atom with R⁴ representing a hydroxyl group oraralkyloxy,

a group of compounds wherein R¹ represents a hydroxyl group oraralkyloxy (preferably phenyl C₁₋₄ alkyl), R² represents —CH₂OR⁵ andboth R³ and R⁴ represent a hydrogen atom,

a group of compounds wherein R¹ represents a hydroxyl group,C_(1≢)alkoxy or C₁₋₆ alkylcarbonyloxy, R² represents —CH₂OR⁵ (wherein R⁵preferably represents a hydrogen atom or aralkyl, more preferably phenylC₁₋₄ alkyl) and R³ and R⁴ represent a hydrogen atom,

a group of compounds wherein R¹ represents a hydroxyl group, R²represents —CH₂OR⁵ (preferably R⁵=H), R³ represents C₁₋₆ alkyl and R₄represent a hydroxyl group,

a group of compounds wherein R¹ represents a hydroxyl group, R²represents —CH₂OR⁵ (preferably R⁵ =H), R³ represents a hydrogen atom andR⁴ represents hydroxy C₁₋₆ alkyl or —COOR¹¹ (preferably R¹¹=H).

a group of compounds wherein R¹ represents optionally substitutedaralkyloxy (preferably phenyl C₁₋₄ alkyloxy), R² represents —CH₂OR⁵,wherein R⁵ represents a hydrogen atom, C₁₋₆ alkyl (preferably C₁₋₄alkyl), or C₁₋₆ alkylcarbonyl (preferably C₁₋₄ alkylcarbonyl), and R³and R⁴ represent a hydrogen atom,

a group of compounds wherein R¹ represents a hydroxyl group, R²represents —CH₂OR⁵, wherein R⁵ represents C₁₋₆ alkyl (preferably C₁₋₄alkyl) or C₁₋₆ alkylcarbonyl (preferably C₁₋₄ alkylcarbonyl), and R³ andR⁴ represent a hydrogen atom,

a group of compounds wherein R¹ represents a hydroxyl group, C₁₋₆ alkoxy(preferably C₁₋₄ alkoxy), or C₁₋₆ alkylcarbonyloxy (preferably C₁₋₄alkylcarbonyloxy), R² represents —CH₂OR⁵, wherein R⁵ representsoptionally substituted aralkyl (preferably phenyl C₁₋₄ alkyl), and R³and R⁴ represent a hydrogen atom,

a group of compounds wherein R¹ represents C₁₋₆ alkoxy (preferably C₁₋₄alkoxy) or C₁₋₆ alkylcarbonyloxy (preferably C₁₋₄ alkylcarbonyloxy), R²represents —CH₂OH and R³ and R⁴ represent a hydrogen atom,

a group of compounds wherein R¹ represents a hydroxyl group, R²represents —CH₂OR⁵ (preferably R⁵=H) and R³ and R⁴ combine with eachother to form a methylene group, and

a group of compounds wherein R¹ and R² combine with each other to form—O—CR⁹(R¹⁰)—OCH₂— (preferably R⁹=R¹⁰=methyl) and — — — represents adouble bond.

Further novel compounds, of the present invention, represented by theformula (II) are:

a compound wherein R¹ represents a hydroxyl group, R² represents—COO—C₁₋₆ alkyl (preferably —COO—C₁₋₄ alkyl), R³ represents a hydrogenatom and R⁴ represents a hydroxyl group,

a compound wherein R¹ represents C₁₋₆ alkoxy (preferably C₁₋₄ alkyl), R²represents —CH₂OH, R³ represents a hydrogen atom and R⁴ represents ahydroxyl group,

a compound wherein R¹ represents aralkyloxy (preferably phenyl C₁₋₄alkyloxy), R² represents formyl, carboxyl, —COO—C₁₋₆ alkyl (preferably—COO—C₁₋₄ alkyl), or —CH₂OR⁵, wherein R⁵ represents a hydrogen atom,C₁₋₆ alkyl (preferably C₁₋₄ alkyl) or C₁₋₆ alkylcarbonyl (preferablyC₁₋₄ alkylcarbonyl), R³ represents a hydrogen atom and R⁴ representsaralkyloxy (preferably phenyl C₁₋₄ alkyloxy), and

a compound wherein R¹ represents a hydroxyl group or C₁₋₆ alkoxy(preferably C₁₋₄ alkoxy), R² represents aralkyloxy (preferably phenylC₁₋₄ alkyloxy), R³ represents a hydrogen atom and R⁴ representsaralkyloxy (preferably phenyl C₁₋₄ alkyloxy).

Preparation of compounds

Some of the compounds represented by the formula (I) are known in theart, and may be prepared by processes previously described.

Preferred production processes will be described. The compoundsrepresented by the formula (II) are embraced in the compoundsrepresented by the formula (I) and, hence, can be prepared by thefollowing production processes.

In the following processes, preferably, any functional group which doesnot participate in contemplated reactions is preferably protected. Inthis case, it would be apparent to a person having ordinary skill in theart that protective groups for this purpose may be those known in theart.

Process (A)

Among the triterpene derivatives represented by the formula (I), acompound represented by the following formula (Ia), wherein R^(3a)represents a C₁₋₆ alkyl group, can be prepared in accordance with thefollowing scheme:

In the step (i), the compound (III) is oxidized to give the compound(IV). Oxidizing agents usable herein include, for example, pyridiniumchromate, pyridinium dichromate, manganese dioxide, anddimethylsulfoxide (DMSO) oxidizing regents, such as DMSO-oxalylchloride. Preferably, the oxidizing agent is used in an amount of 1 to 5equivalents based on the compound (III). The reaction may be carried outin an inert solvent (for example, dichloromethane, chloroform, diethylether, or tetrahydrofuran (THF)) in the temperature range of −78 to 40°C.

In the step (ii), the compound of the formula (IV) is reacted with thecompound of the formula (V), wherein R^(3a) represents a C₁₋₆ alkylgroup, M represents a metal, X represents a halogen or lithium, m is aninteger of 1 to 4 and n is an integer of 0 to 3, to give the compound ofthe formula (1a). The reaction may be carried out in an inert solvent(for example, diethyl ether, THF, benzene, toluene, hexane,dimethylformamide (DMF), hexamethylphosphoric triamide, ordichloromethane) in the temperature range of from −78 to 20° C.Preferably, the compound of the formula (V) is used in an amount of 1 to3 equivalents based on the compound of the formula (IV). Preferredexamples of metals represented by M include lithium, magnesium, tin,zinc, boron, silicon, aluminum, and copper.

In the reactions according to the above scheme, preferably, the compoundrepresented by the formula (III), wherein R¹ represents a hydroxyl groupand R² represents hydroxymethyl, is reacted with, for example,CR⁹R¹⁰(OMe)₂, to protect a hydroxyl group present in R¹ and R² and thenoxidized. The protective group may be removed by hydrolysis. Thehydrolysis may be generally carried out in the presence of a mineralacid, such as hydrochloric acid or sulfuric acid, or a Lewis acid, suchas BF₃Et₂, in a solvent (for example, methanol, ethanol, isopropanol(IPA), water, dichloromethane or chloroform) in the temperature range offrom 0 to 120° C.

Process (B)

Among the triterpene derivatives represented by the formula (I), acompound represented by the following formula (Ib) can be prepared inaccordance with the following scheme:

The compound of the formula (VI) may be oxidized with a suitableoxidizing agent to give the compound of the formula (1b). Oxidizingagents usable herein include, for example, pyridinium chromate,pyridinium dichromate, manganese dioxide, and dimethylsulfoxide (DMSO)oxidizing regents, such as DMSO-oxalyl chloride. Preferably, theoxidizing agent is used in an amount of 1 to 5 equivalents based on thecompound (VI). The reaction may be carried out in an inert solvent (forexample, dichloromethane, chloroform, diethyl ether, or tetrahydrofuran(THF)) in the temperature range of −78 to 40° C.

Process (C)

Among the triterpene derivatives represented by the formula (I), acompound represented by the following formula (Ic) can be prepared byoxidizing the compound of the formula (1b):

The reaction may be carried out in an inert solvent (for example, DMF,tert-butanol, acetone, or water) in the presence of an oxidizing agent(for example, pyridinium dichromate, Jones reagent, potassiumpermanganate, or sodium chlorite) in the temperature range of from 0 to60° C. In general, the oxidizing agent is preferably used in an amountof 1 to 30 equivalents based on the compound of the formula (Ib).

Process (D)

Among the triterpene derivatives represented by the formula (I), acompound represented by the following formula (Id) can be prepared bythe following process.

In the step (i), the compound of the formula (IV) is reacted with amethylenating agent (for example, Ph₃P═CH₂, Tabbe reagent, or Nystedreagent) to give the compound of the formula (VII). Preferably, themethylenating agent is used in an amount of 1 to 10 equivalents based onthe compound of the formula (IV). The reaction may be carried out in aninert solvent (for example, dichloromethane, chloroform, diethyl ether,THF, DMF, or DMSO) in the temperature range of from −78 to 40° C. Ifnecessary, a Lewis acid, such as titanium tetrachloride, may be added tothe reaction system to accelerate the reaction.

Then, in the step (ii), the compound (VII) may be catalytically reducedin the presence of a catalyst to give the compound of the formula (Id).The reaction may be carried out in an inert solvent (for example,methanol, ethanol, THF, dioxane, dichloromethane, chloroform, or water),usually in a hydrogen atmosphere of 1 to 4 atm, at room temperature. Forexample, palladium-carbon, palladium black, or palladiumhydroxide-carbon may be used as the catalyst in an amount of 0.1 to 0.6equivalent.

Process (E)

Among the triterpene derivatives represented by the formula (I), acompound represented by the formula (Ie), wherein R⁴ represents formyl,can be prepared by the following process.

In the step (i), the compound of the formula (IV) is methylenatedaccording to the process (D).

Then, in the step (ii), the compound of the formula (IV) is reacted witha hydroboration reagent, and the reaction product is then oxidized togive the compound of the formula (IX). Hydroboration reagents usableherein include, for example, BH₃-THF, thexylborane,9-borabicyclo(3,3,1)nonane. Preferably, this reagent is used in anamount of 1 to 10 equivalents based on the compound of the formula (IV).The reaction may be carried out in an inert solvent (for example,diethyl ether or THF) in the temperature range of from 0° C. to roomtemperature.

In the oxidation reaction, an oxidizing agent (for example, sodiumhydroxide or 30% hydrogen peroxide) is added to the reaction mixture,and the reaction is carried out at 0° C.

The compound of the formula (IX) thus obtained is converted, byoxidation in the step (iii), to the compound of the formula (Ie).Oxidizing agents usable herein include, for example, pyridiniumchromate, pyridinium dichromate, manganese dioxide, anddimethylsulfoxide (DMSO) oxidizing regents, such as DMSO-oxalylchloride. Preferably, the oxidizing agent is used in an amount of 1 to 5equivalents based on the compound (IX). The reaction may be carried outin an inert solvent (for example, dichloromethane, chloroform, diethylether, or THF) in the temperature range of −78 to 40° C.

Process (F)

Among the triterpene derivatives represented by the formula (I), acompound represented by the following formula (If) can be prepared byoxidizing the compound of the formula (Ie):

Oxidizing agents usable herein include pyridinium dichromate, Jonesreagent, potassium permanganate, and sodium chlorite. The oxidizingagent is used in an amount of 1 to 30 equivalents based on the compoundof the formula (Ie). The oxidation reaction is carried out in an inertsolvent (for example, DMF, tert-butanol, acetone, or water) in thetemperature range of from 0 to 60° C.

Process (G)

Among the triterpene derivatives represented by the formula (I), acompound represented by the following formula (Ig), wherein — — —represents a double bond, can be prepared by the following process:

In the step (i), the compound of the formula (III) may be reacted withthe compound of the formula (X): Z—SO₂Cl, wherein Z represents a C₁₋₆alkyl group or an aryl group, to give the compound of the formula (XI).Preferred examples of the compound of the formula (X) includemethanesulfonyl chloride, benzenesulfonyl chloride, andp-toluenesulfonyl chloride. The reaction is carried out in the presenceof a suitable base in an inert solvent (for example, benzene, toluene,dichloromethane, chloroform, diethyl ether, THF, or DMF) in thetemperature range of 0 to 60° C. Preferred bases include, for example,triethylamine, pyridine, 4-dimethylaminopyridine, and, preferably, thecompound of the formula (X) and the base are used in an amount of 1 to 3equivalents based on the compound of the formula (III).

In the step (ii), the compound of the formula (XI) thus obtained may bereduced with a suitable reducing agent to give the compound of theformula (Ig). Reducing agents usable herein include, for example,triethylboronlithium hydride. Preferably, the reducing agent is used inan amount of 1 to 5 equivalents based on the compound of the formula(XI). The reaction is carried out in an inert solvent (for example,diethyl ether, THF, benzene, toluene, or dichloromethane) in thetemperature range of from −78 to 80° C.

Process (H)

Among the triterpene derivatives represented by the formula (I), acompound represented by the following formula (Ih) can be prepared byreducing the compound of the formula (Ig):

The reduction reaction may be carried out by catalytically reducing thecompound (Ig) in the presence of a catalyst. The reaction may be carriedout in an inert solvent (for example, methanol, ethanol, THF, dioxane,dichloromethane, chloroform, or water), usually in a hydrogen atmosphereof 1 to 4 atm, at room temperature. For example, palladium-carbon,palladium black, or palladium hydroxide-carbon may be used as thecatalyst in an amount of 0.1 to 0.6 equivalent.

Process (I)

Among the triterpene derivatives represented by the formula (I), acompound represented by the formula (Ii), wherein R¹² is as definedabove, can be prepared by the following process:

The compound of the formula (III) is reacted with the compound of theformula (XII): R¹²Y, wherein R¹² is as defined above and Y represents ahalogen atom, in the presence of a base to give the compound of theformula (Ii). The reaction is carried out in an inert solvent (forexample, chloroform, dichloromethane, diethyl ether, THF, benzene,toluene, DMF, or DMSO) in the temperature range of from −78 to 60° C.Bases usable herein include, for example, pyridine, triethylamine,4-dimethylaminopyridine, sodium hydride, potassium hydride,n-butyllithium, NaCH₂SOCH₃, and tert-BuOk. Preferably, the base and thecompound of the formula (XII) are used in an amount of 1 to 10equivalents based on the compound of the formula (III).

Process (J)

Among the triterpene derivatives represented by the formula (I), acompound represented by the following formula (Ij1), wherein R⁵ is asdefined above, and a compound of the formula (Ij2), wherein R^(1a)represents C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl, or aralkyl), can be preparedby the following process:

In the step (i), the compound of the formula (VI) is reacted withArCH(OMe)₂ or ArCHO in the presence of an acid to give the compound ofthe formula (XIV). The reaction may be carried out in an inert solvent(for example, benzene, toluene, xylene, dichloromethane, chloroform,diethyl ether, THF, DMF, or acetone) in the temperature range of 0 to120° C. Acid usable herein include hydrochloric acid, sulfuric acid,p-toluenesulfonic acid, and camphorsulfonic acid. Preferably, ArCH(OMe)₂or ArCHO is used in an amount of 1 to 30 equivalents based on thecompound of the formula (VI).

In the step (ii), the compound of the formula (XIV) thus obtained may bereduced with a suitable reducing agent to give the compound of theformula (XV) and the compound of the formula (XVI). Reducing agentsusable herein include aluminum hydride, diisobutyl aluminum hydride,lithiumaluminum hydride-aluminum chloride. Preferably, the reducingagent is used in an amount of 1 to 10 equivalents based on the compoundof the formula (XIX). The reaction is carried out in an inert solvent(for example, dichloromethane, chloroform, benzene, toluene, or diethylether) in the temperature range of from −30 to 40° C.

Subsequently, in the step (iii), the compound of the formula (XVI) thusobtained is reacted with a compound represented by the formula: R⁵Y,wherein R⁵ is as defined above and Y represents a halogen atom, in thepresence of a base to give a compound of the formula (XVII). Basesusable herein include, for example, sodium hydride, potassium hydride,n-butyllithium, NaCH₂SOCH₃, tert-BuOk, triethylamine, pyridine, and4-dimethylaminopyridine. Preferably, the base and the compound of theformula: R⁵Y are used in an amount of 1 to 10 equivalents based on thecompound of the formula (XVI). The reaction is carried out in an inertsolvent (for example, diethyl ether, THF, benzene, toluene, DMF, DMSO,or dichloromethane) at −78 to 60° C.

In the step (iv), the compound of the formula (XVII) thus obtained maybe catalytically reduced in the presence of a catalyst to give thecompound of the formula (Ij1). The reaction may be carried out in aninert solvent (for example, methanol, ethanol, THF, dioxane,dichloromethane, chloroform, or water), usually in a hydrogen atmosphereof 1 to 4 atm, at room temperature. For example, palladium-carbon,palladium black, or palladium hydroxide-carbon may be used as thecatalyst in an amount of 0.1 to 0.6 equivalent.

In the step (v), the compound of the formula (XV) may be reacted with acompound of the formula: R^(1a)Y, wherein R^(1a) is as defined above andY is a halogen atom, in the presence of a based to give the compound ofthe formula (XVIII). Bases usable herein include, for example, sodiumhydride, potassium hydride, n-butyllithium, NaCH₂SOCH₃, tert-BuOk,triethylamine, pyridine, and 4-dimethylaminopyridine. Preferably, thebase and the compound of the formula: R⁵Y are used in an amount of 1 to10 equivalents based on the compound of the formula (XVI). The reactionis carried out in an inert solvent (for example, diethyl ether, THF,benzene, toluene, DMF, DMSO, or dichloromethane) at −78 to 60° C.

In the step (vi), the compound of the formula (XVIII) thus obtained maybe catalytically reduced in the presence of a catalyst to give thecompound of the formula (Ij1). The reaction may be carried out in aninert solvent (for example, methanol, ethanol, THF, dioxane,dichloromethane, chloroform, or water), usually in a hydrogen atmosphereof 1 to 4 atm, at room temperature. For example, palladium-carbon,palladium black, or palladium hydroxide-carbon may be used as thecatalyst in an amount of 0.1 to 0.6 equivalent.

Process (K)

Among the triterpene derivatives represented by the formula (I), acompound of the formula (Ik), wherein R⁷ and R⁸ are as defined above,can be prepared from the compound of the formula (1b) by the followingprocess:

The compound of the formula (Ib) and a compound of the formula R⁷R⁸NH,wherein R⁷ and R⁸ are as defined above, are subjected to catalyticreduction in the presence of a catalyst. The reaction may be carried outin an inert solvent (for example, methanol, ethanol, THF, dioxane,dichloromethane, chloroform, or water), usually in a hydrogen atmosphereof 1 to 4 atm, at room temperature. For example, palladium-carbon,palladium black, or palladium hydroxide-carbon may be used as thecatalyst in an amount of 0.1 to 0.6 equivalent.

Process (L)

Among the triterpene derivatives represented by the formula (I), acompound of the formula (Il), wherein R⁶ is as defined above, can beprepared from the compound of the formula (Ic) by esterificationaccording to the following process:

The esterification can be carried out by reacting the compound of theformula (Ic) with R⁶X, wherein R⁶ represents a C₁₋₆ alkyl group and Xrepresents a halogen, in the presence of a base, or with R⁶OH, whereinR⁶ is as defined above, and a condensing agent in the presence of abase, or with diazomethane, trimethylsilyldiazomethane or the like togive the compound of the formula (II). Bases usable herein includesodium hydrogencarbonate, sodium carbonate, sodium hydride, cesiumcarbonate, triethylamine, pyridine, 4-dimethylaminopyridine, and DBU.Condensing agents usable herein include cyclohexylcarbodiimide.Preferably, the base, R⁶X, R⁶OH, and condensing agent are used in anamount of 1 to 2 equivalents based on the compound of the formula (Ic).The reaction may be carried out in an inert solvent (for example,diethyl ether, THF, benzene, toluene, DMF, dichloromethane, or MeOH) inthe temperature range of 0 to 40° C.

EXAMPLES

The present invention will be described in more detail with reference tothe following examples, though it is not limited to these examples only.

Compounds 1 to 73 listed in Table 1 described below were synthesized.Compounds 1, 4, 24, 25, 27, and 28 were produced according to a processdescribed in Chem. Pharm. Bull., 36, 153 (1988), and compound 9 wasproduced according to a process described in Chem. Pharm. Bull., 24, 121(1976), Chem. Pharm. Bull., 31, 664 (1983), and Chem. Pharm. Bull., 31,674 (1983).

Example 1 22-Oxolean-12-ene-3β,24(4β)-diol (Compound 2)

Oxalyl chloride (0.4 ml) was dissolved in 10 ml of dichloromethane, andthe solution was cooled to −78° C. A solution of 0.65 ml of DMSO in 2 mlof dichloromethane was added to the cooled solution, and the mixture wasthen stirred for 10 min. A solution of 1.5 g of compound 1 in 5 ml ofdichloromethane was dropwise added to the reaction mixture, and themixture was then stirred at −78° C. for 15 min. To the reaction mixturewas added 2.1 ml of triethylamine, and the mixture was stirred at −78°C. for 5 min. The temperature of the reaction mixture was graduallyraised to 0° C., diluted with water, and extracted with dichloromethane.The organic layer was washed with saturated sodium hydrogencarbonate anddried over magnesium sulfate. After the inorganic salt was removed byfiltration, the filtrate was concentrated under reduced pressure. Theresultant solid was purified by column chromatography on silica gel(n-hexane:ethyl acetate=10:1). The colorless solid (1.3 g) thus obtainedwas dissolved in 30 ml of methanol, 1 N hydrochloric acid was addedthereto, and the mixture was stirred at room temperature for 30 min. Thereaction mixture was diluted with dichloromethane, washed with water,and dried over magnesium sulfate. After the inorganic salt was removedby filtration, the filtrate was concentrated under reduced pressure togive 1.2 g (yield 86%) of compound 2 as a colorless solid.

NMR (CDCl₃) δ ppm 0.86 (3H, s), 0.90 (3H, s), 0.94 (3H, s), 0.99 (3H,s), 1.00 (3H, s), 1.22 (3H, s), 1.26 (3H, s), 0.88-2.58 (23H, m), 3.35,4.21 (1H each, both d, J=11.1 Hz), 3.45 (1H, dd, J=4.4 Hz), 5.30 (1H,t-like).

MS EI (m/z): 456 (M⁺)

Example 2 22α-Methylolean-12-ene-3β,22β,24(4β)-triol (Compound 3)

In 5 ml of anhydrous THF was dissolved 100 mg (0.22 mmol) of compound 2,and 670 μl of a diethyl ether solution of methyllithium (1.8 mol/l) wasadded thereto at −78° C. The mixture was stirred for one hr whilegradually raising the temperature to 0° C. Water was added thereto, andthe mixture was extracted with ethyl acetate. The organic layer wasdried over magnesium sulfate. After the inorganic salt was removed byfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by column chromatography on silica gel(n-hexane:ethyl acetate 2:1) to give 62 mg (yield 60%) of compound 3.

NMR (CDCl₃) δ ppm 0.86 (3H, s), 0.89 (6H, s), 0.96 (3H, s), 1.07 (3H,s), 1.10 (3H, s), 1.16 (3H, s), 1.25 (3H, s), 0.84-2.86 (24H, m), 3.35(1H, t, J=10.2 Hz), 3.44 (1H, m), 4.20 (1H, d, J=11.1 Hz), 5.23 (1H,t-like).

MS EI (m/z): 472 (M⁺)

Example 3 3β,22β-Dibenzyloxy-24(4β)-triphenylmethyloxymethylolean-12-ene(Compound 5)

In 5 ml of anhydrous DMF was dissolved 95 mg of compound 4.83 mg of 60%sodium hydride was added to the solution, and the mixture was thenstirred at room temperature for 1.5 hr. Thereafter, 75 μl of benzylbromide was added to the reaction mixture, and the mixture was thenstirred at 40° C. for 5 hr. The reaction mixture was diluted with ethylacetate, washed thrice with water, and dried over magnesium sulfate.After the inorganic salt was removed by filtration, the filtrate wasconcentrated under reduced pressure. The oil thus obtained was purifiedby column chromatography on silica gel (n-hexane:ethyl acetate=10:1) togive 118 mg (yield 65%) of compound 5 as a colorless solid.

NMR (CDCl₃) δ ppm 0.33 (3H, s), 0.82 (3H, s), 0.88 (3H, s), 0.92 (3H,s), 1.03 (3H, s), 1.08 (3H, s), 1.34 (3H, s), 0.70-2.15 (21H, m),2.93-2.97 (1H, m), 3.06-3.07 (1H, m), 3.17 (1H, d, J=9.2 Hz), 3.53 (1H,d, J=9.2 Hz), 4.32 (1H, d, J=11.9 Hz), 4.38 (1H, d, J=11.9 Hz), 4.61(1H, d, J=11.9 Hz), 4.63 (1H, d, J=11.9 Hz), 5.17 (1H, t-like),7.19-7.50 (25H, m).

MS FD (m/z): 881(M⁺+1)

Example 4 3β,22β-Dibenzyloxyolean-12-en-24(4β)-ol (Compound 6)

In a mixed solution of 10 ml of methanol and 2 ml of acetone wasdissolved 440 mg of compound 5. Concentrated hydrochloric acid (0.4 ml)was further added thereto, and the mixture was refluxed for 30 min.After water was added to the reaction mixture, the mixture wasneutralized with 1 N sodium hydroxide and extracted thrice withdichloromethane. The organic layer was dried over magnesium sulfate.After the inorganic salt was removed by filtration, the filtrate wasconcentrated under reduced pressure. The oil thus obtained was purifiedby column chromatography on silica gel (n-hexane:ethyl acetate=10:1) togive 231 mg (yield 72%) of compound 6 as an oil.

NMR (CDCl₃) δ ppm 0.88 (3H, s), 0.89 (3H, s), 0.93 (3H, s), 0.94 (3H,s), 1.05 (3H, s), 1.11 (3H, s), 1.21 (3H, s), 0.85-2.18 (22H, m),3.07-3.08 (1H, m), 3.18-3.24 (2H, m), 4.16 (1H, d, J=10.5 Hz), 4.32 (1H,d, J=11.7 Hz), 4.39 (1H, d, J=11.7 Hz), 4.62 (1H, d, J=11.7 Hz), 4.67(1H, d, J=11.7 Hz), 5.22 (1H, t-like), 7.26-7.34 (10H, m).

MS SIMS (m/z): 639 (M⁺+1)

Example 5 3β,22β-Dibenzyloxy-24(4β)-oxolean-12-ene (Compound 7)

Oxalyl chloride (0.15 ml) was dissolved in 4 ml of dichloromethane, andthe solution was then cooled to −78° C. A solution of 0.23 ml of DMSO indichloromethane was added to the cooled solution, and the mixture wasthen stirred for 10 min. A solution of 128 mg of compound 6 in 2 ml ofdichloromethane was added to the reaction mixture, and the mixture wasthen stirred at −78° C. for 15 min. To the reaction mixture was added0.7 ml of triethylamine, and the mixture was stirred at −78° C. for 5min. The temperature of the reaction mixture was gradually raised to 0°C., diluted with water, and extracted with dichloromethane. The organiclayer was washed with saturated sodium hydrogencarbonate and dried overanhydrous magnesium sulfate. After the inorganic salt was removed byfiltration, the filtrate was concentrated under reduced pressure. Theresultant oil was purified by column chromatography on silica gel(n-hexane:ethyl acetate=10:1) to give 104 mg (yield 82%) of compound 7as a colorless foam substance.

NMR (CDCl₃) δ ppm 0.83 (3H, s), 0.89 (3H, s), 0.93 (3H, s), 0.94 (3H,s), 1.04 (3H, s), 1.10 (3H, s), 1.21 (3H, s), 0.85-2.18 (21H, m), 3.07(1H, dd, J=3.1 Hz, 3.1 Hz), 3.18 (1H, dd, J=5.1 Hz, 5.1 Hz), 4.20, 4.61(1H, each, both d, J=11.7 Hz), 5.23 (1H, t-like), 7.22-7.35 (10H, m),10.07 (1H, s).

MS SIMS (m/z): 637 (M⁺+1)

Example 6 24(4β)-Oxolean-12-ene-3β,22β-diol (Compound 8)

In 1 ml of methanol was dissolved 30 mg of compound 7, and 30 mg of 20%Pd(OH)₂—C was added to the solution. The mixture was subjected tocatalytic reduction at room temperature under atmospheric pressure forone hr. After the reaction mixture was filtered through Celite, thefiltrate was concentrated under reduced pressure to give 21 mg (yield100%) of compound 8.

NMR (CDCl₃) β ppm 0.88 (6H, s), 0.92 (3H, s), 1.00 (3H, s), 1.04 (3H,s), 1.13 (3H, s), 1.30 (3H, s), 0.97-2.12 (22H, m), 3.12-3.20 (1H, m),3.44 (1H, t, J=5.1 Hz), 5.26 (1H, t-like), 9.76 (1H, d, J=2.4 Hz).

MS EI (m/z): 456 (M⁺)

Example 7 3β,22β-Dibenzyloxyolean-12-en-24(4β)-oic acid (Compound 10)

In 6 ml of tert-butanol was dissolved 20 mg of compound 7, and 1.5 ml of2-methyl-2-butene was added thereto. A solution of 250 mg of sodiumchlorite and 250 mg of monosodium phosphate in 2.5 ml of water was addedto the reaction solution, and the mixture was then stirred at roomtemperature overnight. After the reaction mixture was concentrated underreduced pressure, the concentrate was extracted with ethyl acetate. Theorganic layer was dried over magnesium sulfate. After the inorganic saltwas removed by filtration, the filtrate was concentrated under reducedpressure. The oil thus obtained was purified by column chromatography onsilica gel (n-hexane:ethyl acetate=5:1) to give 6.8 mg (yield 34%) ofcompound 10 as colorless solid.

NMR (CDCl₃) β ppm 0.89 (3H, s), 0.94 (3H, s), 0.95 (3H, s), 1.02 (3H,s), 1.04 (3H, s), 1.10 (3H, s), 1.40 (3H, s), 0.85-2.19 (21H, m),3.05-3.09 (1H, m), 3.15-3.19 (1H, m), 4.32 (1H, d, J=11.83 Hz), 4.56(1H, d, J=11.83 Hz), 4.61 (1H, d, J=11.83 Hz), 4.85 (1H, d, J=11.83 Hz),5.23 (1H, t-like), 7.23-7.52 (10H, m).

MS EI (m/z): 652 (M⁺)

Example 8 3β,22β-Dihydroxyolean-12-en-24(4β)-oic acid (Compound 11)

Compound 10 (5 mg) was dissolved in a mixed solvent of 0.5 ml ofmethanol and 0.5 ml of dichloromethane, and 5 mg of 20% Pd(OH)₂—C wasadded to the solution. The mixture was subjected to catalytic reductionat room temperature under atmospheric pressure for 45 min. After thereaction mixture was filtered through Celite, the filtrate wasconcentrated under reduced pressure to give 3.3 mg (yield 92%) ofcompound 11 as a foam substance.

NMR (CDCl₃) δ ppm 0.85 (3H, s), 0.92 (3H, s), 0.93 (3H, s), 1.00 (3H,s), 1.02 (3H, s), 1.11 (3H, s), 1.41 (3H, s), 0.87-2.08 (21H, m),3.09-3.12 (1H, m), 3.40-3.43 (1H, m), 5.27 (1H, t-like).

MS SIMS (m/z): 473 (M⁺+1)

Example 9 22-Methyleneolean-12-ene-3β,24(4β)-diol (Compound 12)

In 12 ml of Nysted reagent was suspended 1.0 g of compound 2, and thesuspension was cooled to −78° C. A solution (5 ml) of titaniumtetrachloride (1.0 M) in dichloromethane solution was added by portionsto the cooled suspension. The temperature of the reaction mixture wasreturned to room temperature, and the reaction mixture was then stirredovernight. While the reaction mixture was stirred under ice cooling, 6 Nhydrochloric acid was added by portions thereto. The mixture wasextracted thrice with chloroform, and the organic layer was then driedover anhydrous magnesium sulfate. After the inorganic salt was removedby filtration, the filtrate was concentrated under reduced pressure. Theresultant solid was purified by column chromatography on silica gel(n-hexane:ethyl acetate=2:1) to give 518 mg (yield 52%) of compound 12as a colorless solid.

NMR (CDCl₃) δ ppm 0.78 (3H, s), 0.89 (3H, s), 0.90 (3H, s), 0.95 (3H,s), 1.03 (3H, s), 1.17 (3H, s), 1.25 (3H, s), 0.84-2.20 (21H, m), 2.39(1H, brs), 2.72 (1H, brs), 3.32-3.37 (1H, m), 3.43-3.46(1H, m), 4.21(1H, d, J=11.10 Hz), 5.27 (1H, t-like).

MS EI (m/z): 454 (M⁺)

Example 10 22-Methylolean-12-ene-3β,24(4β)-diol (Compound 13)

Compound 12 (29 mg) was dissolved in a mixed solvent of 1 ml of methanoland 9 ml of dichloromethane, and 20 mg of 20% Pd(OH)₂—C was added to thesolution. The mixture was subjected to catalytic reduction at roomtemperature under atmospheric pressure for one hr. After the reactionmixture was filtered through Celite, the filtrate was concentrated underreduced pressure to give 27 mg (yield 93%) of compound 13 as a colorlesssolid.

NMR (CDCl₃) δ ppm 0.80 (3H, s), 0.86 (6H, s), 0.89 (3H, s), 0.90 (3H,s), 0.93 (3H, s). 1.13 (3H, s), 1.25 (3H, s), 0.64-1.94 (22H, m), 3.35(1H, d, J=10.52 Hz), 3.42-3.46 (1H, m), 4.20 (1H, d, J=10.52 Hz), 5.17(1H, t-like).

MS EI (m/z): 456 (M⁺)

Example 11 22-Hydroxymethylolean-12-ene-3β,24(4β)-diol (Compound 14)

In 7 ml of anhydrous THF was dissolved 300 mg of compound 12, and 3.3 mlof a solution of BH₃-THF (1.0 M) in THF was added to the solution. Themixture was then stirred at room temperature overnight. While thereaction mixture was stirred under ice cooling, 3 ml of 10% hydroxidesolution was added thereto, and 3 ml of 30% hydrogen peroxide was addedthereto over a period of 5 min. The mixture was stirred under icecooling for 1.5 hr, water was added thereto. The mixture was extractedwith ethyl acetate. The organic layer was washed with saturated salineand then dried over magnesium sulfate. After the inorganic salt wasremoved by filtration, the filtrate was concentrated under reducedpressure. The residue was purified by column chromatography on silicagel (n-hexane:ethyl acetate=1:1) to give 245 mg (yield 79%) of compound14.

NMR (CDCl₃) δ ppm 0.70 (3H, s), 0.90 (3H, s), 0.91 (3H, s), 0.92 (3H,s), 0.96 (3H, s), 1.05 (3H, s), 1.25 (3H, s), 0.84-1.87 (22H, m),3.28-3.35 (2H, m), 3.42-3.47 (1H, m), 3.65-3.70 (1H, m), 4.20 (1H, d,J=11.10 Hz), 5.25 (1H, t-like).

MS EI (m/z): 472 (M⁺)

Example 12 22-Hydroxymethyl-3,24(4β)-isopropylidenedioxyolean-12-ene(Compound 15)

In 13 ml of acetone was dissolved 200 mg of compound 14, and 10 ml of2,2-dimethoxypropane and 3 mg of camphorsulfonic acid were added to thesolution. The mixture was then stirred at 37° C. overnight. After thereaction mixture was concentrated under reduced pressure, the residuewas dissolved in ethyl acetate, a small amount of silica gel was addedthereto. The mixture was then stirred at room temperature for two days.The reaction solution was concentrated under reduced pressure. Theresidue was purified by column chromatography on silica gel(n-hexane:ethyl acetate=5:1) to give 105 mg (yield 48%) of compound 15as a colorless solid.

NMR (CDCl₃) δ ppm 0.70 (3H, s), 0.91 (3H, s), 0.95 (3H, s), 0.96 (3H,s), 1.06 (3H, s), 1.17 (3H, s), 1.21 (3H, s), 1.37 (3H, s), 1.43 (3H,s), 0.87-2.04 (22H, m), 3.21 (1H, d, J=11.54 Hz), 3.32 (1H, t, J=10.5Hz), 3.45 (1H, dd, J=4.62 Hz, 9.24 Hz), 3.67 (1H, dd, J=10.52 Hz, 10.52Hz), 4.03 (1H, d, J=11.54 Hz), 5.27 (1H, t-like).

MS EI (m/z): 512 (M⁺)

Example 13 22-Formyl-3β,24(4β)-isopropylidenedioxyolean-12-ene (Compound16)

The procedure of Example 5 was repeated, except that 105 mg of compound15 was used as the starting compound. Thus, 91 mg (yield 87%) ofcompound 16 was prepared.

NMR (CDCl₃) δ ppm 0.87 (3H, s), 0.90 (3H, s), 0.96 (3H, s), 0.99 (3H,s), 1.10 (3H, s), 1.18 (3H, s), 1.21 (3H, s), 1.37 (3H, s), 1.43 (3H,s), 0.88-2.10 (22H, m), 3.22 (1H, d, J=11.72 Hz), 3.45-3.48 (1H, m),4.03 (1H, d, J=11.72 Hz), 5.30 (1H, s), 9.80 (1H, s).

MS EI (m/z) δ ppm 510 (M⁺)

Example 14 22-Formylolean-12-ene-3β,24(4β)-diol (Compound 17)

Compound 16 (10 mg) was dissolved in a mixed solvent of 1.0 ml ofmethanol and 1.0 ml of dichloromethane, 50 μl of 1 N hydrochloric acidwas added to the solution under ice cooling. The mixture was thenstirred for 10 min. The reaction mixture was diluted with ethyl acetate,washed with water and a saturated aqueous sodium hydrogencarbonate, andthen dried over anhydrous magnesium sulfate. After the inorganic saltwas removed by filtration, the filtrate was concentrated under reducedpressure. The residue was dissolved in a mixed solvent of 2 ml ofacetone and 0.2 ml of water, a small amount of camphorsulfonic acid wasadded thereto. The mixture was then stirred at room temperatureovernight. After the reaction solution was concentrated under reducedpressure, the residue was dissolved in dichloromethane. The solution waswashed with water and saturated aqueous sodium hydrogencarbonate andthen dried over magnesium sulfate. After the inorganic salt was removedby filtration, the filtrate was concentrated under reduced pressure togive 7 mg (yield 78%) of compound 17 as a colorless solid.

NMR (CDCl₃) δ ppm 0.79 (3H, s), 0.83 (6H, s), 0.84 (3H, s), 0.92 (3H,s), 1.02 (3H, s), 1.18 (3H, s), 0.77-2.03 (22H, m), 2.41 (1H, brs), 2.67(1H, brs), 3.30 (1H, brs), 3.37 (1H, d, J=11.43 Hz), 4.13 (1H, d,J=11.43 Hz) 5.21 (1H, t-like), 9.72 (1H, s).

MS FD (m/z): 471 (M⁺+1)

Example 15 22—Carboxy-3β,24(4β)-isopropylidenedioxyolean-12-ene(Compound 18)

The procedure of Example 7 was repeated, except that 20 mg of compound16 was used as the starting compound. Thus, 21 mg (yield 99%) ofcompound 18 was prepared.

NMR (CDCl₃) δ ppm 0.83 (3H, s), 0.90 (3H, s), 0.95 (3H, s), 0.99 (3H,s), 1.07 (3H, s), 1.17 (3H, s), 1.21 (3H, s), 1.38 (3H, s), 1.44 (3H,s), 0.87-2.24 (22H, m), 3.22 (1H, d, J=11.73 Hz), 3.45-3.48 (1H, m),4.03 (1H, d, J=11.73 Hz), 5.30 (1H, s).

MS EI (m/z): 526 (M⁺)

Example 16 22-Carboxyolean-12-ene-3β,24(4β)-diol (Compound 19)

Compound 18 (20 mg) was dissolved in a mixed solvent of 2 ml of methanoland 1 ml of dichloromethane, 0.2 ml of 1 N hydrochloric acid was addedto the solution under ice cooling. The mixture was then stirred for 10min. The reaction mixture was diluted with ethyl acetate, washed withwater, and dried over magnesium sulfate. After the inorganic salt wasremoved by filtration, the filtrate was concentrated under reducedpressure. The resultant solid was purified by column chromatography onsilica gel (n-hexane:methanol=10:1) to give 12 mg (yield 64%) ofcompound 19 as a colorless foam substance.

NMR (CDCl₃) δ ppm 0.81 (3H, s), 0.90 (9H, s), 0.98 (3H, s), 1.06 (3H,s), 1.23 (3H, s), 0.83-2.21 (22H, m), 3.32 (1H, d, J=11.1 Hz), 3.40 (1H,dd, J=4.16 Hz, 11.38 Hz), 4.20 (1H, d, J=11.1 Hz), 5.28 (1H, t-like).

MS FD (m/z): 486 (M⁺)

Example 17 3β,24(4β)-Isopropylidenedioxy-22β-tosyloxyolean-12-ene(Compound 20)

Compound 1 (500 mg) was dissolved in pyridine, 287 mg ofp-toluenesulfonyl chloride and a catalytic amount of4-dimethylaminopyridine were added to the solution. The mixture was thenstirred at room temperature overnight. After water was added to thereaction mixture, the mixture was extracted with ethyl acetate. Theorganic layer was dried over magnesium sulfate. After the inorganic slatwas removed by filtration, the filtrate was concentrated under reducedpressure to give 654 mg (yield 100%) of compound 20 as a colorlesssolid.

NMR (CDCl₃) δ ppm 0.76 (3H, s), 0.84 (9H, s), 0.94 (3H, s), 0.96 (3H,s), 1.10 (3H, s), 1.14 (3H, s), 1.21 (3H, s), 1.37 (3H, s), 1.44 (3H,s), 0.78-2.10 (21H, m), 2.45 (3H, s), 3.22 (1H, d, J=11.65 Hz),3.43-3.46 (1H, m), 4.03 (1H, d, J=11.65 Hz), 4.34-4.37 (1H, m), 5.22(1H, t-like).

MS FD (m/z): 652 (M⁺)

Example 18 3β,24(4β)-Isopropylidenedioxyolean-12,21-diene (Compound 21)

To 65 mg of compound 20 was added 2 ml of triethylboronlithium hydride(1.0 M THF solution) under ice cooling, and the mixture was then stirredat 65° C. for one hr. The temperature of the reaction mixture wasreturned to room temperature. After water was added thereto, the mixturewas extracted with ethyl acetate. The organic layer was dried overmagnesium sulfate. After the inorganic salt was removed by filtration,the filtrate was concentrated under reduced pressure. The resultantsolid was purified by column chromatography on silica gel(n-hexane:ethyl acetate=10:1) to give 38 mg (yield 79%) of compound 21as a colorless solid.

NMR (CDCl₃) δ ppm 0.88 (3H, s), 0.96 (9H, s), 0.98 (3H, s), 0.99 (3H,s), 1.12 (3H, s), 1.17 (3H, s), 1.22 (3H, s), 1.38 (3H, s), 1.44 (3H,s), 0.90-2.13 (19H, m), 3.23 (1H, d, J=11.54 Hz), 3.45-3.48 (1H, m),4.05 (1H, d, J=11.54 Hz), 5.20-5.32 (3H, m).

MS EI (m/z): 480 (M⁺)

Example 19 Olean-12,21-diene-3β,24(4β)-diol (Compound 22)

Compound 21 (48 mg) was dissolved in a mixed solvent of 1 ml of methanoland 1 ml of dichloromethane, 0.5 ml of 1 N hydrochloric acid was addedto the solution. The mixture was then stirred for one hr. The reactionmixture was diluted with dichloromethane, washed with water, and driedover magnesium sulfate. After the inorganic salt was removed byfiltration, the filtrate was concentrated under reduced pressure to give36 mg (yield 82%) of compound 22 as a colorless solid.

NMR (CDCl₃) δ ppm 0.87 (3H, s), 0.90 (3H, s), 0.94 (3H, s), 0.95 (3H,s), 0.98 (3H, s), 1.11 (3H, s), 1.25 (3H, s), 0.84-2.13 (19H, m), 2.36(1H, d, J=4.10 Hz), 2.68 (1H, d, J=6.67 Hz), 3.32-3.37 (1H, m),3.43-3.48 (1H, m), 4.21 (1H, d, J=11.28 Hz), 5.20-5.30 (3H, m).

MS EI (m/z): 440 (M⁺)

Example 20 Olean-12-ene-3β,24(4β)-diol (Compound 23)

Compound 21 (30 mg) was dissolved in a mixed solvent of 2 ml of methanoland 1 ml of dichloromethane, 5 mg of 20% Pd(OH)₂—C was added to thesolution. The mixture was then subjected to catalytic reduction underatmospheric pressure overnight. After the reaction mixture was filtered,the filtrate was concentrated under reduced pressure to give 26 mg(yield 93%) of compound 23 as a colorless solid.

NMR (CDCl₃) δ ppm 0.82 (3H, s), 0.87 (6H, s), 0.89 (3H, s), 0.93 (3H,s), 1.13 (3H, s), 1.25 (3H, s), 1.25 (3H, s), 0.78-2.03 (23H, m), 2.37(1H, d, J=4.16 Hz), 2.71 (1H, dd, J=2.50 Hz, 8.88 Hz), 3.32-3.37 (1H,m), 3.42-3.48 (1H, m), 4.21 (1H, d, J=10.88 Hz), 5.18 (1H, t-like).

MS EI (m/z): 442 (M⁺)

Example 21 3β,24(4β)-Isopropylidenedioxy-22β-methoxyolean-12-ene(Compound 26)

Compound 1 (300 mg) was dissolved in 5 ml of THF, 130 mg of 55% sodiumhydride was added thereto, and the mixture was then stirred at roomtemperature for one hr. Thereafter, the 2 ml of methyl iodide wasfurther added to the reaction solution. The mixture was stirredovernight. The reaction mixture was diluted with ethyl acetate, washedwith water, and dried over magnesium sulfate. After the inorganic saltwas removed by filtration, the filtrate was concentrated under reducedpressure. The residue was purified by column chromatography on silicagel (n-hexane:ethyl acetate=10:1) to give 285 mg (yield 93%) of compound26 as a colorless foam substance.

NMR (CDCl₃) δ ppm 0.86 (3H, s), 0.90 (3H, s), 0.99 (3H, s), 1.00 (3H,s), 1.11 (3H, s), 1.15 (3H, s), 1.22 (3H, s), 1.37 (3H, s), 1.44 (3H,s), 0.83-2.10 (21H, m), 2.80-2.83 (1H, m), 3.23 (1H, d, J=11.8 Hz), 3.28(3H, s), 3.44-3.47 (1H, m), 4.06 (1H, d, J=11.8 Hz), 5.23 (1H, t-like).

MS FD (m/z): 512 (M⁺).

Example 22 22β-Methoxyolean-12-ene-3β,24(4β)-diol (Compound 27)

Compound 26 (280 mg) was dissolved in THF, 0.66 ml of boron trifluorideethyl ether was added to the solution, and the mixture was stirred atroom temperature for one hr. The reaction mixture was neutralized with asaturated aqueous sodium hydrogencarbonate solution and extracted withethyl acetate. The organic layer was dried over magnesium sulfate. Afterthe inorganic salt was removed by filtration, the solution wasconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel (n-hexane:ethyl acetate=2:1) to give 203 mg(yield 79%) of compound 27 as a colorless solid.

NMR (CDCl₃) δ ppm 0.85 (3H, s), 0.89 (3H, s), 0.90 (3H, s), 0.94 (3H,s), 1.00 (3H, s), 1.11 (3H, s), 1.25 (3H, s), 0.80-2.10 (21H, m),2.80-2.82 (1H, m), 3.28 (3H, s), 3.33 (1H, d, J 11.1 Hz), 3.42-3.45 (1H,m), 5.22 (1H, t-like).

MS EI (m/z): 472 (M⁺)

Example 23 22β-Benzyloxy-3β,24(4β)-isopropylideneoxyolean-12-ene(Compound 30)

Compound 1 (50 mg) was dissolved in 2 ml of anhydrous DMF, 20 mg of 60%sodium hydride was added to the solution, and the mixture was stirred atroom temperature for one hr. Thereafter, 85 μ of benzyl bromide wasadded thereto, and the mixture was stirred overnight. The reactionmixture was diluted with ethyl acetate, washed with water, and driedover magnesium sulfate. After the inorganic salt was removed byfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by column chromatography on silica gel(n-hexane:ethyl acetate=10:1) to give 34 mg (yield 58%) of compound 30as a colorless solid.

NMR (CDCl₃) δ ppm 0.89 (3H, s), 0.94 (3H, s), 0.99 (3H, s), 1.04 (3H,s), 1.12 (3H, s), 1.15 (3H, s), 1.22 (3H, s), 1.37 (3H, s), 1.44 (3H,s), 0.87-2.17 (21H, m), 3.07 (1H, dd, J=3.05 Hz, 6.38 Hz), 3.22 (1H, d,J=11.65 Hz), 3.45 (1H, dd, J=4.44 Hz, 9.44 Hz), 4.05 (1H, d, J=11.65Hz), 4.32 (1H, d, J=11.65 Hz), 4.61 (1H, d, J=11.65 Hz), 5.24 (1H,t-like), 7.23-7.37 (5H, m).

MS EI (m/z): 588 (M⁺)

Example 24 22β-Benzyloxyolean-12-ene-3β,24(4β)-diol (Compound 31)

Compound 30 (34 mg) was dissolved in a mixed solvent of 2 ml of methanoland 1 ml of dichloromethane, 0.5 ml of 1 N hydrochloric acid was addedto the solution, and the mixture was stirred at room temperature for 30min. After saturated sodium hydrogencarbonate was added to the reactionmixture, the mixture was extracted twice with dichloromethane. Theorganic layer was dried over magnesium sulfate. After the inorganic saltwas removed by filtration, the filtrate was concentrated under reducedpressure to give 28 mg (yield 86%) of compound 31 as a colorless solid.

NMR (CDCl₃) δ ppm 0.89 (6H, s), 0.93 (3H, s), 0.94 (3H, s), 1.04 (3H,s), 1.11 (3H, s), 1.25 (3H, s), 0.83-2.18 (21H, m), 2.38 (1H, brs), 2.69(1H, brs), 3.07 (1H, d, J=3.08 Hz, 6.16 Hz), 3.32-3.36 (1H, m),3.43-3.46 (1H, m), 4.20 (1H, d, J=10.51 Hz), 4.32 (1H, d, J=11.80 z),4.61 (1H, d, J=11.80 Hz), 5.22 (1H, t-like), 7.23-7.38 (5H, m).

MS EI (m/z): 548 (M⁺)

Example 25 22β-Ethoxy-3β,24(4β)-isopropylidenedioxyolean-12-ene(Compound 32)

The procedure of Example 23 was repeated, except that 100 mg of compound1 and 80 μl of ethyl iodide were used as the starting compounds. Thus,61 mg (yield 58%) of compound 32 was prepared as a colorless foamsubstance.

NMR (CDCl₃) δ ppm 0.87 (3H, s), 0.89 (3H, s), 0.99 (3H, s), 1.01 (3H,s), 1.12 (3H, s), 1.13 (3H, t, J=7.18 Hz), 1.15 (3H, s), 1.22 (3H, s),1.37 (3H, s), 1.44 (3H, s), 0.90-2.11 (21H, m), 2.89 (1H, dd, J=2.82 Hz,6.42 Hz), 3.23 (1H, d, J=11.28 Hz), 3.22-3.30 (1H, m), 3.46 (1H, dd,J=4.36 Hz, 9.24 Hz), 3.52-3.60 (1H, m), 4.05 (1H, d, J=11.28 Hz), 5.23(1H, t-like).

MS EI (m/z): 526 (M⁺)

Example 26 22β-Ethoxyolean-12-ene-3β,24(4β)-diol (Compound 33)

The procedure of Example 24 was repeated, except that 61 mg of compound32 was used as the starting compound. Thus, 49 mg (yield 88%) ofcompound 33 was prepared as a colorless solid.

NMR (CDCl₃) δ ppm 0.86 (3H, s), 0.89 (3H, s), 0.90 (3H, s), 0.95 (3H,s), 1.01 (3H, s), 1.12 (3H, s), 1.14 (3H, t, J=7.22 Hz), 1.25 (3H, s),0.84-2.13 (21H, m), 2.40 (1H, d, J=4.16 Hz), 2.70 (1H, d, J=8.87 Hz),2.89 (1H, dd, J=2.77 Hz, 6.38 Hz), 3.22-3.30 (1H, m), 3.35 (1H, t,J=9.71 Hz), 3.42-3.47 (1H, m), 3.52-3.60 (1H, m), 4.21 (1H, d, J=9.71Hz), 5.21 (1H, t-like).

MS EI (m/z): 486 (M⁺)

Example 27 22β-Allyloxy-3β,24(4β)-isopropylidenedioxyolean-12-ene(Compound 34)

The procedure of Example 23 was repeated, except that 50 mg of compound1 and 46 μl of allyl iodide were used as the starting compounds. Thus,35 mg (yield 65%) of compound 34 was prepared as a colorless solid.

NMR (CDCl₃) δ ppm 0.89 (6H, s), 0.99 (3H, s), 1.01 (3H, s), 1.12 (3H,s), 1.16 (3H, s), 1.22 (3H, s), 1.37 (3H, s), 1.44 (3H, s), 0.87-2.15(21H, m), 2.98 (1H, dd, J=2.78 Hz, 6.38 Hz), 3.23 (1H, d, J=11.65 Hz),3.45 (1H, d, J=4.44 Hz, 9.43 Hz), 3.77-3.82 (1H, m), 4.02-4.07 (2H, m),5.08-5.12 (1H, m),5.22-5.28 (2H, m), 5.85-5.93 (1H, m).

MS EI (m/z): 538 (M⁺)

Example 28 22β-Allyloxyolean-12-ene-3β,24(4β)-diol (Compound 35)

The procedure of Example 24 was repeated, except that 33 mg of compound34 was used as the starting compound. Thus, 27 mg (yield 88%) ofcompound 35 was prepared as a colorless solid.

NMR (CDCl₃) δ ppm 0.88 (3H, s), 0.89 (3H, s), 0.90 (3H, s), 0.94 (3H,s), 1.01 (3H, s), 1.11 (3H, s), 1.25 (3H, s), 0.84-2.75 (23H, m),2.97-2.99 (1H, m), 3.32-3.38 (1H, m), 3.42-3.48 (1H, m), 3.77-3.83 (1H,m), 4.02-4.08 (1H, m), 4.21 (1H, d, J=11.09 Hz), 5.09-5.13 (1H, m),5.21-5.28 (2H, m), 5.86-5.94 (1H, m).

MS EI (m/z): 498 (M⁺)

Example 29 22β-Benzoyloxy-3β,24(4β)-isopropylidenedioxyolean-12-ene(Compound 36)

Compound 1 (50 mg) was dissolved in 5 ml of dichloromethane, 18 mg of4-dimethylaminopyridine and 17 μl of benzoyl chloride were added to thesolution, and the mixture was then refluxed overnight. The reactionmixture was diluted with dichloromethane, washed with water, and driedover magnesium sulfate. After the inorganic salt was removed byfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by column chromatography on silica gel(n-hexane:ethyl acetate=3:1) to give 24 mg (yield 40%) of compound 36 asa colorless solid.

NMR (CDCl₃) δ ppm 0.91 (3H, s), 0.93 (3H, s), 1.00 (3H, s), 1.06 (3H,s), 1.16 (3H, s), 1.18 (3H, s), 1.23 (3H, s), 1.38 (3H, s), 1.44 (3H,s), 0.88-2.37 (21H, m), 3.23 (1H, d, J=11.54 Hz), 3.47 (1H, dd, J=4.44Hz, 9.48 Hz), 4.05 (1H, d, J=11.54 Hz), 4.93 (1H, t, J=3.85 Hz), 5.33(1H, t-like), 7.45 (2H, t, J=6.70 Hz), 7.55 (1H, t, J=6.70 Hz), 8.05(2H, d, J=6.70 Hz).

MS EI (m/z): 602 (M⁺)

Example 30 22β-Benzoyloxyolean-12-ene-3β,24(4β)-diol (Compound 37)

The procedure of Example 24 was repeated, except that 24 mg of compound36 was used as the starting compound. Thus, 19 mg (yield 83%) ofcompound 37 was prepared as a colorless solid.

NMR (CDCl₃) δ ppm 0.83 (3H, s), 0.84 (3H, s), 0.86 (3H, s), 0.88 (3H,s), 0.98 (3H, s), 1.11 (3H, s), 1.18 (3H, s), 0.78-2.78 (23H, m), 3.28(1H, t, J=10.77 Hz), 3.35-3.40 (1H, m), 4.14 (1H, d, J=10.77 Hz), 4.86(1H, t-like), 5.25 (1H, t-like), 7.37 (2H, t, J=7.18 Hz), 7.48 (1H, t,J=7.18 Hz), 7.98 (2H, d, J=7.18 Hz).

MS EI (m/z): 562 (M⁺)

Example 31 3β,24(4β)-Isopropylidenedioxy-22β-propionyloxyolean-12-ene(Compound 38)

The procedure of Example 29 was repeated, except that 100 mg of compound1 and 27 μl of propionyl chloride were used as the starting compounds.Thus, 73 mg (yield 66%) of compound 38 was prepared as a colorlesssolid.

NMR (CDCl₃) δ ppm 0.82 (3H, s), 0.90 (3H, s), 0.99 (3H, s), 1.00 (3H,s), 1.44 (3H, t, J=7.69 Hz), 1.15 (3H, s), 1.16 (3H, s), 1.23 (3H, s),1.38 (3H, s), 1.44 (3H, s), 0.88-2.23 (21H, m), 2.31 (2H, dq, J=3.34 Hz,7.69 Hz), 3.24 (1H, d, J=11.54 Hz), 3.46 (1H, dd, J=4.36 Hz, 9.23 Hz),4.05 (1H, d, J=11.54 Hz), 4.66 (1H, t, J=3.59 Hz), 5.27 (1H, t-like).

MS EI (m/z): 554 (M⁺)

Example 32 22β-Propionyloxyolean-12-ene-3β,24(4β)-diol (Compound 39)

The procedure of Example 24 was repeated, except that 73 mg of compound38 was used as the starting compound. Thus, 56 mg (yield 82%) ofcompound 39 was prepared as a colorless solid.

NMR (CDCl₃) δ ppm 0.81 (3H, s), 0.89 (6H, s), 0.95 (3H, s), 1.00 (3H,s), 1.14 (3H, t, J=7.49 Hz), 1.15 (3H, s), 1.25 (3H, s), 0.84-2.75 (25H,m), 3.32-3.37 (1H, m), 3.43-3.46 (1H, m), 4.21 (1H, d, J=11.10 Hz), 4.66(1H, t, J=2.89 Hz), 5.26 (1H, t-like).

MS EI (m/z): 514 (M⁺)

Example 33 3β,24(4β)-Isopropylidenedioxy-22β-valeryloxyolean-12-ene(Compound 40)

The procedure of Example 29 was repeated, except that 50 mg of compound1 and 36 μl of valeryl chloride were used as the starting compounds.Thus, 32 mg (yield 55%) of compound 40 was prepared as a colorlesssolid.

NMR (CDCl₃) δ ppm 0.82 (3H, s), 0.90 (3H, s), 0.92 (3H, t, J=7.21 Hz),0.99 (3H, s), 1.00 (3H, s), 1.15 (3H, s), 1.16 (3H, s), 1.23 (3H, s),1.38 (3H, s), 1.44 (3H, s), 0.78-2.33 (27H, m), 3.23 (1H, d, J=11.65Hz), 3.46 (1H, dd, J=4.44 Hz, 9.43 Hz), 4.06 (1H, d, J=11.65 Hz), 4.66(1H, t, J=3.88 Hz), 5.28 (1H, t-like).

MS EI (m/z): 582 (M⁺)

Example 34 22β-Valeryloxyolean-12-ene-3β,24(4β)-diol (Compound 41)

The procedure of Example 24 was repeated, except that 31 mg of compound40 were used as the starting compound. Thus, 17 mg (yield 59%) ofcompound 41 was prepared as a colorless solid.

NMR (CDCl₃) δ ppm 0.81 (3H, s), 0.89 (6H, s), 0.92 (3H, t, J=7.21 Hz),0.95 (3H, s), 1.00 (3H, s), 1.15 (3H, s), 1.25 (3H, s), 0.84-2.71 (29H,m), 3.31-3.38 (1H, m), 3.42-3.49 (1H, m), 4.21 (1H, d, J=10.82 Hz), 4.66(1H, t, J=3.61 Hz), 5.26 (1H, t-like).

MS EI (m/z): 542 (M⁺)

Example 3522β-Trans-crotonyloxy-3β,24(4β)-isopropylidenedioxyolean-12-ene(Compound 42)

The procedure of Example 29 was repeated, except that 50 mg of compound1 and 30 μl of trans-crotonyl chloride were used as the startingcompounds. Thus, 9 mg (yield 16%) of compound 42 was prepared as acolorless solid.

NMR (CDCl₃) δ ppm 0.82 (3H, s), 0.90 (3H, s), 0.99 (3H, s), 1.00 (3H,s), 1.15 (6H, s), 1.23 (3H, s), 1.38 (3H, s), 1.44 (3H, s), 0.88-2.25(24H, m), 3.23 (1H, d, J=11.65 Hz),3.47 (1H, dd, J=4.44 Hz, 9.44 Hz),4.05 (1H, d, J=11.65 Hz), 4.71 (1H, t, J=3.61 Hz), 5.28 (1H, t-like),5.81-5.86 (1H, m), 6.90-6.99 (1H, m).

MS EI (m/z): 566 (M⁺)

Example 36 22β-Trans-crotonyloxyolean-12-ene-3β,24(4β)-diol (Compound43)

The procedure of Example 24 was repeated, except that 9 mg of compound42 was used as the starting compound. Thus, 5 mg (yield 59%) of compound43 was prepared as a colorless solid.

NMR (CDCl₃) δ ppm 0.81 (3H, s), 0.89 (6H, s), 0.94 (3H, s), 0.99 (3H,s), 1.15 (3H, s), 1.25 (3H, s), 0.84-2.74 (26H, m), 3.31-3.38 (1H, m),3.42-3.47 (1H, m), 4.20 (1H, d, J=10.77 Hz), 4.71 (1H, t, J=3.59 Hz),5.26 (1H, t-like), 5.81-5.85 (1H, m), 6.89-6.98 (1H, m).

MS EI (m/z): 526 (M⁺)

Example 37 22β-Cinnamoyloxy-3β,24(4β)-isopropylidenedioxyolean-12-ene(Compound 44)

The procedure of Example 29 was repeated, except that 50 mg of compound1 and 50 mg of cinnamoyl chloride were used as the starting compounds.Thus, 39 mg (yield 63%) of compound 44 was prepared as a colorlesssolid.

NMR (CDCl₃) δ ppm 0.88 (3H, s), 0.92 (3H, s), 1.00 (3H, s), 1.05 (3H,s), 1.16 (3H, s), 1.17 (3H, s), 1.23 (3H, s), 1.38 (3H, s), 1.44 (3H,s), 0.90-2.32 (21H, m), 3.24 (1H, d, J=11.54 Hz), 3.47 (1H, dd, J=4.36Hz, 9.23 Hz), 4.05 (1H, d, J=11.54 Hz), 4.80 (1H, t, J=3.59 Hz), 5.31(1H, t-like), 6.43 (1H, d, J=15.90 Hz), 7.37-7.40 (3H, m), 7.52-7.55(2H, m), 7.66 (1H, d, J=15.90 Hz).

MS EI (m/z): 628 (M⁺)

Example 38 22β-Cinnamoyloxyolean-12-ene-3β,24(4β)-diol (Compound 45)

The procedure of Example 24 was repeated, except that 30 mg of compound44 was used as the starting compound. Thus, 23 mg (yield 84%) ofcompound 45 was prepared as a colorless solid.

NMR (CDCl₃) δ ppm 0.87 (3H, s), 0.89 (3H, s), 0.91 (3H, s), 0.95 (3H,s), 1.04 (3H, s), 1.16 (3H, s), 1.25 (3H, s), 0.85-2.70 (23H, m),3.31-3.38 (1H, m), 3.42-3.49 (1H, m), 4.21 (1H, d, J=11.02 Hz), 4.79(1H, t-like), 5.29 (1H, t-like), 6.42 (1H, d, J=15.90 Hz), 7.36-7.40(3H, m), 7.51-7.55 (2H, m), 7.65 (1H, d, J=15.90 Hz).

MS EI (m/z): 588 (M⁺)

Example 39 3β,22β-Dibenzyloxy-24(4β)-N-methylamino-olean-12-ene(Compound 46)

Compound 7 (50 mg) was dissolved in a mixed solvent of 2 ml of methanoland 2 ml of dichloromethane, 0.1 ml of a 40% aqueous methylaminesolution and 10 mg of 20% Pd(OH)₂—C were added to the solution. Themixture was then subjected to catalytic reduction under atmosphericpressure for 2 hr. After the reaction mixture was filtered throughCelite, the filtrate was concentrated under reduced pressure. Theresidue was purified by column chromatography on silica gel(dichloromethane:methanol=5:1) to give 13 mg (yield 25%) of compound 46as a colorless solid.

NMR (CDCl₃) δ ppm 0.89 (3H, s), 0.90 (3H, s), 0.93 (3H, s), 0.94(3H, s),1.04 (3H, s), 1.10 (3H, s), 1.42 (3H, s), 0.87-2.19 (22H, m), 2.58 (3H,s), 3.00 (1H, d, J=12.20 Hz), 3.06-3.09 (1H, m), 3.15 (1H, d, J=12.20Hz), 3.24-3.28 (1H, m), 4.32 (1H, d, J=11.65 Hz), 4.41 (1H, d, J=10.82Hz), 4.61 (1H, d, J=11.65 Hz), 4.68 (1H, d, J=10.82 Hz), 5.21 (1H,t-like), 7.28-7.40 (10H, m).

MS TSP (m/z): 652 (M⁺+1)

Example 40 24(4β)-N-Methylamino-olean-12-ene-3β,22β-diol (Compound 47)

Compound 46 (13 mg) was dissolved in a mixed solvent of 1 ml of methanoland 1 ml of dichloromethane, 10 mg of 20% Pd(OH)₂—C was added to thesolution. The mixture was then subjected to catalytic reduction underatmospheric pressure for 5 hr. After the reaction mixture was filteredthrough Celite, the filtrate was concentrated under reduced pressure togive 4 mg (yield 49%) of compound 47 as a colorless solid.

NMR (CDCl₃) δ ppm 0.86 (3H, S), 0.92 (6H, s), 0.95 (3H, s), 1.03 (3H,s), 1.10 (3H, s), 1.33 (3H, s), 0.88-2.10 (23H, m), 2.68 (3H, s), 2.90(1H, d, J 12.57 Hz), 3.18 (1H, d, J=12.57 Hz), 3.39-3.45 (3H, m), 5.25(1H, t-like).

MS TSP (m/z): 472 (M⁺+1)

Example 41 3β,24(4β)-Benzylidenedioxyolean-12-ene (Compound 48)

Compound 23 (500 mg) was dissolved in 12 ml of anhydrous DMF, 0.2 ml ofbenzaldehydediacetoacetal and a catalytic amount of camphorsulfonic acidwere added to the solution. The mixture was then stirred at 45° C.overnight. Benzaldehydedimethylacetal (0.1 ml) was further addedthereto, and the mixture was stirred at 45° C. for 8 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated sodiumhydrogencarbonate, and dried over magnesium sulfate. After the inorganicsalt was removed by filtration, the filtrate was concentrated underreduced pressure. The residue was purified by column chromatography onsilica gel (n-hexane:ethyl acetate=10:1) to give 498 mg (yield 83%) ofcompound 48 as a colorless solid.

NMR (CDCl₃) δ ppm 0.84 (3H, s), 0.88 (6H, s), 0.97 (3H, s), 1.07 (3H,s), 1.15 (3H, s), 1.48 (3H, s), 0.79-2.48 (23H, m), 3.60-3.67 (2H, m),4.30 (1H, d, J=11.54 Hz), 5.19 (1H, t-like), 5.78 (1H, s), 7.30-7.52(5H, m).

MS TSP (m/z): 531 (M⁺+1)

Example 42 3β-Benzyloxyolean-12-en-24(4β)-ol (Compound 49) and24(4β)-benzyloxyolean-12-en-3β-ol (Compound 50)

Compound 48 (200 mg) was dissolved in 3 ml of anhydrous toluene, and 1.5ml of a solution of diisobutylaluminum hydride (1.0 M) in toluene wasdropwise added to the solution at −25 to −20° C. The mixture was stirredfor one hr, and further stirred for 3 hr while gradually returning thetemperature of the mixture to room temperature. After water was added tothe reaction mixture, the mixture was extracted with ethyl acetate. Theorganic layer was dried over magnesium sulfate. After the inorganic saltwas removed by filtration, the solution was concentrated under reducedpressure. The residue was purified by column chromatography on silicagel (n-hexane:ethyl acetate=10:1) to give, as a colorless solid, 61 mg(yield 30%) of compound 49 and 96 mg (yield 48%) of compound 50.

Compound 49

NMR (CDCl₃) δ ppm 0.82 (3H, s), 0.87 (6H, s), 0.89 (3H, s), 0.94 (3H,s), 1.12 (3H, s), 1.21 (3H, s), 0.78-2.01 (23H, m), 3.17-3.28 (3H, m),4.16 (1H, d, J=10.34 Hz), 4.40 (1H, d, J=11.38 Hz), 4.67 (1H, d, J=11.38Hz), 5.18 (1H, t-like), 7.25-7.37 (5H, m).

MS FAB (m/z): 533 (M⁺+1)

Compound 50:

NMR (CDCl₃) δ ppm 0.82 (3H, s), 0.85 (3H, s), 0.86 (3H, s), 0.87 (3H,s), 0.92 (3H, s), 1.12 (3H, s), 1.28 (3H, s), 0.80-2.01 (23H, m),3.22-3.31 (2H, m), 3.94 (1H, d, J=7.21 Hz), 4.00 (1H, d, J=9.16 Hz),4.48 (2H, d, J=2.77 Hz), 5.17 (1H, t-like), 7.26-7.37 (5H, m).

MS EI (m/z): 532 (M⁺)

Example 43 24(4β)-Acetoxy-3β-benzyloxyolean-12-ene (Compound 51)

Compound 49 (16 mg) was dissolved in 0.5 ml of dichloromethane, 0.5 mlof pyridine and 0.5 ml of acetic anhydride were added to the solution,and the mixture was stirred at room temperature overnight. After icewater was added to the reaction mixture, the mixture was extracted withethyl acetate. The extract was dried over magnesium sulfate. After theinorganic salt was removed by filtration, the filtrate was concentratedunder reduced pressure. The residue was purified by columnchromatography on silica gel (n-hexane:ethyl acetate=5:1) to give 14 mg(yield 81%) of compound 51 as a colorless solid.

NMR (CDCl₃) δ ppm 0.83 (3H, s), 0.87 (6H, s), 0.96 (3H, s), 0.97 (3H,s), 1.12 (3H, s), 1.15 (3H, s), 0.78-2.00 (23H, m), 1.98 (3H, s), 3.03(1H, dd, J=4.16 Hz, 11.65 Hz), 4.19 (1H, d, J=11.93 Hz), 4.35 (1H, d,J=11.93 Hz), 4.37 (1H, d, J=11.65 Hz), 4.65 (1H, d, J=11.65 Hz), 5.19(1H, t-like), 7.27-7.34 (5H, m).

MS EI (m/z): 574 (M⁺)

Example 44 24(4β)-Acetoxyolean-12-en-3β-ol (Compound 52)

The procedure of Example 8 was repeated, except that 14 mg of compound51 was used as the starting compound. Thus, 8 mg (yield 65%) of compound52 was prepared as a colorless solid.

NMR (CDCl₃) δ ppm 0.83 (3H, s), 0.87 (6H, s), 0.93 (3H, s), 0.95 (3H,s), 1.13 (3H, s), 1.15 (3H, s), 0.78-2.08 (24H, m), 2.06 (3H, s), 3.30(1H, dd, J=4.71 Hz, 11.38 Hz), 4.14 (1H, d, J=11.65 Hz), 4.35 (1H, d,J=11.65 Hz), 5.18 (1H, t-like).

MS EI (m/z): 484 (M⁺)

Example 45 3β-Benzyloxy-24(4β)-methoxyolean-12-ene (Compound 53)

The procedure of Example 21 was repeated, except that 26 mg of compound49 and 30 μl of methyl iodide was used as the starting compound. Thus,17 mg (yield 61%) of compound 53 was prepared as a colorless solid.

NMR (CDCl₃) δ ppm 0.83 (3H, s), 0.87 (6H, s), 0.96(3H, s), 1.01 (3H, s),1.12 (3H, s), 1.15 (3H, s), 0.75-2.00 (23H, m), 2.98 (1H, dd, J=4.10 Hz,11.79 Hz), 3.27 (3H, s), 3.39 (1H, d, J=9.75 Hz), 3.65 (1H, d, J=9.75Hz), 4.42 (1H, d, J=11.80 Hz), 4.63 (1H, d, J=11.80 Hz), 5.19 (1H,t-like), 7.25-7.36 (5H, m).

MS EI (m/z): 546 (M⁺)

Example 46 24(4β)-Methoxyolean-12-en-3β-ol (Compound 54)

The procedure of Example 8 was repeated, except that 17 mg of compound53 was used as the starting compound. Thus, 12 mg (yield 86%) ofcompound 54 was prepared as a colorless solid.

NMR (CDCl₃) δ ppm 0.82 (3H, s), 0.86 (3H, s), 0.87 (3H, s), 0.91 (3H,s), 0.94 (3H, s), 1.13 (3H, s), 1.22 (3H, s), 0.78-2.02 (23H, m), 3.21(1H, d, J=9.16 Hz), 3.22-3.29 (1H, m), 3.31 (3H, s), 3.89 (1H, d, J=9.16Hz), 3.91-3.95 (1H, m), 5.18 (1H, t-like).

MS EI (m/z): 456 (M⁺)

Example 47 3β-Acetoxy-24(4β)-benzyloxyolean-12-ene (Compound 55)

The procedure of Example 43 was repeated, except that 25 mg of compound50 was used as the starting compound. Thus, 21 mg (yield 79%) ofcompound 55 was prepared as a colorless solid.

NMR (CDCl₃) δ ppm 0.83 (3H, s), 0.87 (3H, s), 0.88 (3H, s), 0.95 (6H,s), 1.07 (3H, s), 1.12 (3H, s), 2.03 (3H, s), 0.78-2.00 (23H, m), 3.49(1H, d, J=9.43 Hz), 3.73 (1H, d, J=9.43 Hz), 4.48 (2H, s), 4.57 (1H, dd,J=4.72 Hz, 11.10 Hz), 5.18 (1H, t-like), 7.25-7.35 (5H, m).

MS EI (m/z): 574 (M⁺)

Example 48 3β-Acetoxyolean-12-en-24(4β)-ol (Compound 56)

The procedure of Example 8 was repeated, except that 21 mg of compound55 was used as the starting compound. Thus, 10 mg (yield 56%) ofcompound 56 was prepared as a colorless solid.

NMR (CDCl₃) δ ppm 0.82 (3H, s), 0.87 (3H, s), 0.88 (3H, s), 0.91 (3H,s), 0.95 (3H, s), 1.09 (3H, s), 1.13 (3H, s), 0.79-2.00 (24H, m), 2.08(3H, s), 3.37-3.43 (1H, m), 4.16 (1H, d, J=12.21 Hz), 4.65 (1H, t,J=8.05 Hz), 5.18 (1H, t-like).

MS EI (m/z): 484 (M⁺)

Example 49 24(4β)-Benzyloxy-3β-methoxyolean-12-ene (Compound 57)

The procedure of Example 23 was repeated, except that 26 mg of compound50 and 30 μl of methyl iodide were used as the starting compounds. Thus,19 mg (yield 70%) of compound 57 was prepared as a colorless solid.

NMR (CDCl₃) δ ppm 0.83 (3H, s), 0.87 (6H, s), 0.94 (6H, s), 1.12 (3H,s), 1.17 (3H, s), 0.79-2.02 (23H, m), 2.72 (1H, dd, J=4.14 Hz, 11.93Hz), 3.34 (3H, s), 3.39 (1H, d, J=9.71 Hz), 3.72 (1H, d, J=9.71 Hz),4.44 (2H, s), 5.18 (1H, t-like), 7.22-7.35 (5H, m).

MS EI (m/z): 546 (M⁺)

Example 50 3β-Methoxyolean-12-en-24(4β)-ol (Compound 58)

The procedure of Example 8 was repeated, except that 19 mg of compound57 was used as the starting compound. Thus, 9 mg (yield 56%) of compound58 was prepared as a colorless solid.

NMR (CDCl₃) δ ppm 0.82 (3H, s), 0.87 (9H, s), 0.94 (3H, s), 1.13 (3H,s), 1.20 (3H, s), 0.79-2.02 (23H, m), 2.93 (1H, dd, J=4.16 Hz, 11.38Hz), 3.18-3.25 (2H, m), 3.36 (3H, s), 4.10-4.14 (1H, m), 5.18 (1H,t-like).

MS EI (m/z): 456 (M⁺)

Example 51 24(4β)-Acetoxy-3β,22β-benzyloxyolean-12-ene (Compound 59)

The procedure of Example 43 was repeated, except that 30 mg of compound6 was used as the starting compound. Thus, 24 mg (yield 76%) of compound59 was prepared as a colorless solid.

NMR (CDCl₃) δ ppm 0.89 (3H, s), 0.94 (3H, s), 0.96 (3H, s), 0.97 (3H,s), 1.05 (3H, s), 1.11 (3H, s), 1.15 (3H, s), 1.98 (3H, s), 0.84-2.18(21H, m), 3.02 (1H, dd, J=4.16 Hz, 11.65 Hz), 3.07 (1H, dd, J=2.77 Hz,6.10 Hz), 4.18 (1H, d, J=11.93 Hz), 4.32 (1H, d, J=11.93 Hz), 4.35 (1H,d, J=11.93 Hz), 4.37 (1H, d, J=11.93 Hz), 4.62 (1H, d, J=11.93 Hz), 4.65(1H, d, J=11.93 Hz), 5.23 (1H, t-like), 7.23-7.36 (10H, m).

MS EI (m/z): 680 (M⁺)

Example 52 24(4β)-Acetoxyolean-12-ene-3β,22β-diol (Compound 60)

The procedure of Example 8 was repeated, except that 24 mg of compound59 was used as the starting compound. Thus, 12 mg (yield 69%) ofcompound 60 was prepared as a colorless solid.

NMR (CDC13) δ ppm 0.87 (3H, s), 0.91 (3H, s), 0.94 (3H, s), 0.96 (3H,s), 1.04 (3H, s), 1.12 (3H, s), 1.16 (3H, s), 0.84-2.12 (23H, m), 2.07(3H, s), 3.27-3.31 (1H, m), 3.44 (1H, t, J=5.28 Hz), 4.14 (1H, d,J=11.66 Hz), 4.35 (1H, d, J=11.66 Hz), 5.25 (1H, t-like).

MS EI (m/z): 500 (M⁺)

Example 53 3β,22β-Dibenzyloxy-24(4β)-propionyloxyolean-12-ene (Compound61)

The procedure of Example 29 was repeated, except that 32 mg of compound6 and 6.8 μl of propionyl chloride were used as the starting compounds.Thus, 22 mg (yield 62%) of compound 61 was prepared as a colorlesssolid.

NMR (CDCl₃) δ ppm 0.89 (3H, s), 0.94 (3H, s), 0.96 (3H, s), 0.97 (3H,s), 1.05 (3H, s), 1.09 (3H, t, J=7.49 Hz), 1.11 (3H, s), 1.15 (3H, s),0.84-2.30 (23H, m), 3.00-3.10 (2H, m), 4.20 (1H, d, J=11.55 Hz),4.30-4.39 (3H, m), 4.60-4.67 (2H, m), 5.23 (1H, t-like), 7.25-7.35 (10H,m).

MS EI (m/z): 694 (M⁺)

Example 54 24(4β)-Propionyloxyolean-12-ene-3β,22β-diol (Compound 62)

The procedure of Example 8 was repeated, except that 21 mg of compound61 was used as the starting compound. Thus, 14 mg (yield 88%) ofcompound 62 was prepared as a colorless solid.

NMR (CDCl₃) δ ppm 0.88 (3H, s), 0.92 (3H, s), 0.94 (3H, s), 0.97 (3H,s), 1.05 (3H, s), 1.12 (3H, s), 1.15 (3H, t, J=7.49 Hz), 1.16 (3H, s),0.89-2.13 (22H, m), 2.35 (2H, q, J=7.49 Hz), 3.29 (1H, dd, J=4.72 Hz,10.82 Hz), 3.42-3.45 (1H, m), 3.49 (1H, s), 4.16 (1H, d, J=11.66 Hz),4.37 (1H, d, J=11.66 Hz), 5.26 (1H, t-like).

MS EI (m/z): 514 (M⁺)

Example 55 3β,22β-Dibenzyloxy-24(4β)-methoxyolean-12-ene (Compound 63)

The procedure of Example 23 was repeated, except that 20 mg of compound6 and 0.3 ml of methyl iodide were used as the starting compounds. Thus,8 mg (yield 38%) of compound 63 was prepared as a colorless solid.

NMR (CDCl₃) δ ppm 0.89 (3H, s), 0.94 (3H, s), 0.97 (3H, s), 1.02 (3H,s), 1.04 (3H, s), 1.10 (3H, s), 1.15 (3H, s), 0.78-2.18 (21H, m),2.95-3.00 (1H, m), 3.05-3.10 (1H, m), 3.27 (3H, s), 3.39 (1H, d, J=9.75Hz), 3.65 (1H, d, J=9.75 Hz), 4.32 (1H, d, J=11.80 Hz), 4.42 (1H, d,J=11.80 Hz), 4.61 (1H, d, J=11.80 Hz), 4.63 (1H, d, J=11.80 Hz), 5.23(1H, t-like), 7.24-7.35 (10H, m).

MS EI (m/z): 652 (M⁺)

Example 56 24(4β)-Methoxyolean-12-ene-3β,22β-diol (Compound 64)

The procedure of Example 8 was repeated, except that 8 mg of compound 63was used as the starting compound. Thus, 6 mg (yield 98%) of compound 64was prepared as a colorless solid.

NMR (CDCl₃) δ ppm 0.87 (3H, s), 0.91 (3H, s), 0.92 (3H, s), 0.95 (3H,s), 1.04 (3H, s), 1.11 (3H, s), 1.22 (3H, s), 0.84-2.12 (23H, m), 3.20(1H, d, J=9.15 Hz), 3.23-3.27 (1H, m), 3.31 (3H, s), 3.42-3.44 (1H, m),3.89 (1H, d, J=9.15 Hz), 5.24 (1H, t-like).

MS EI (m/z): 472 (M⁺)

Example 57 3β,24(4β)-Benzylidenedioxyolean-12-en-22β-ol (Compound 65)

The procedure of Example 41 was repeated, except that 1.00 g of compound9 was used as the starting compound. Thus, 997 mg (yield 83%) ofcompound 65 was prepared as a colorless solid.

NMR (CDCl₃) δ ppm 0.88 (3H, s), 0.92 (3H, s), 0.99 (3H, s), 1.05 (3H,s), 1.08 (3H, s), 1.14 (3H, s), 1.48 (3H, s), 0.90-2.50 (22H, m), 3.44(1H, q, J=5 Hz), 3.60-3.67 (2H, m), 4.30 (1H, d, J=11 Hz), 5.26 (1H,t-like), 5.78 (1H, s), 7.30-7.40 (3H, m), 7.45-7.55 (2H, m).

MS EI (m/z): 546 (M⁺)

Example 58 22β-Benzyloxy-3β,24(4β)-benzylidenedioxyolean-12-ene(Compound 66)

The procedure of Example 23 was repeated, except that 5.42 g of compound65 was used as the starting compound. Thus, 3.24 mg (yield 51%) ofcompound 66 was prepared as a colorless solid.

NMR (CDCl₃) δ ppm 0.90 (3H, s), 0.95 (3H, s), 0.98 (3H, s), 1.05 (3H,s), 1.07 (3H, s), 1.13 (3H, s), 1.48 (3H, s), 0.90-2.50 (21H, m), 3.08(1H, q, J=3 Hz), 3.60-3.66 (2H, m), 4.30 (1H, d, J=l1Hz), 4.32 (1H, d,J=12 Hz), 4.60 (1H, t, J=11 Hz), 5.24 (1H, t-like), 5.78 (1H, s),7.2-7.6 (10H, m).

MS EI (m/z): 636 (M⁺)

Example 59 22β,24(4β)-Dibenzyloxyolean-12-en-3β-ol (Compound 67)

The procedure of Example 42 was repeated, except that 400 g of compound66 was used as the starting compound. Thus, 275 mg (yield 69%) ofcompound 67 and 25.1 mg (yield 6%) of compound 6 were prepared as acolorless solid.

NMR (CDCl₃) δ ppm 0.85 (3H, s), 0.89 (3H, s), 0.93 (6H, s), 1.04 (3H,s), 1.11 (3H, s), 1.28 (3H, s), 0.80-2.20 (22H, m), 3.05-3.08 (1H, m),3.26-3.30 (2H, m), 3.95-4.02 (1H, m), 4.31 (1H, d, J=12 Hz), 4.48 (2H,s), 4.61 (1H, d, J=12 Hz), 5.21 (1H, t-like), 7.26-7.33 (10H, m).

MS EI (m/z): 639 (M⁺)

Example 60 3β-Acetoxy-22β,24(4β)-dibenzyloxyolean-12-ene (Compound 68)

The procedure of Example 43 was repeated, except that 100 g of compound67 was used as the starting compound. Thus, 33 mg (yield 30%) ofcompound 68 was prepared as a colorless solid.

NMR (CDCl₃) δ ppm 0.89 (3H, s), 0.93 (3H, s), 0.95 (6H, s), 1.04 (3H,s), 1.06 (3H, s), 1.10 (3H, s), 2.02 (3H, s), 0.90-2.18 (21H, m),3.05-3.09 (1H, m), 3.48 (1H, d, J=9.71 Hz), 3.73 (1H, d, J=9.71 Hz),4.32 (1H, d, J=11.65 Hz), 4.47 (2H, s), 4.57 (1H, dd, J=4.71 Hz, 11.37Hz), 4.61 (1H, d, J=11.65 Hz), 5.22 (1H, t-like), 7.25-7.36 (10H, m).

MS EI (m/z): 680 (M⁺)

Example 61 3β-Acetoxyolean-12-ene-22β,24(4β)-diol (Compound 69)

The procedure of Example 8 was repeated, except that 32 mg of compound68 was used as the starting compound. Thus, 15 mg (yield 64%) ofcompound 69 was prepared as a colorless solid.

NMR (CDCl₃) δ ppm 0.87 (3H, s), 0.91 (3H, s), 0.92 (3H, s), 0.96 (3H,s), 1.04 (3H, s), 1.09 (3H, s), 1.11 (3H,s), 2.08 (3H, s), 0.90-2.12(23H, m), 3.37-3.46 (2H, m), 4.15 (1H, d, J=11.80 Hz), 4.62-4.67 (1H,m), 5.25 (1H, t-like).

MS EI (m/z): 500 (M⁺)

Example 62 22β,24(4β)-Dibenzyloxy-3β-methoxyolean-12-ene (Compound 70)

The procedure of Example 23 was repeated, except that 100 mg of compound67 was used as the starting compound. Thus, 49 mg (yield 47%) ofcompound 70 was prepared as a colorless solid.

NMR (CDCl₃) δ ppm 0.89 (3H, s), 0.93 (3H, s), 0.94 (3H, s), 0.95 (3H,s), 1.04 (3H, s), 1.10 (3H, s), 1.17 (3H, s), 0.75-2.17 (21H, m), 2.73(1H, dd, J=4.11 Hz, 11.80 Hz), 3.05-3.08 (1H, m), 3.34 (3H, s), 3.38(1H, d, J=9.75 Hz), 3.71 (1H, d, J=9.75 Hz), 4.32 (1H, d, J=12.05 Hz),4.44 (2H, s), 4.61 (1H, d, J=12.05 Hz), 5.22 (1H, t-like), 7.23-7.36(10H, m).

MS TSP (m/z): 653 (M⁺+1)

Example 63 3β-Methoxyolean-12-ene-22β,24(4β)-diol (Compound 71)

The procedure of Example 8 was repeated, except that 48 mg of compound70 was used as the starting compound. Thus, 21 mg (yield 59%) ofcompound 71 was prepared as a colorless solid.

NMR (CDCl₃) δ ppm 0.87 (3H, s), 0.88 (3H, s), 0.91 (3H, s), 0.95 (3H,s), 1.04 (3H, s), 1.11 (3H, s), 1.20 (3H, s), 0.84-2.14 (22H, m), 2.92(1H, dd, J=4.71 Hz, 11.80 Hz), 3.19-3.24 (2H, m), 3.36 (3H, s), 3.44(1H, t-like), 4.10-4.15 (1H, m), 5.25 (1H, t-like).

MS TSP (m/z): 473 (M⁺+1)

Example 64 3β,22β-Dibenzyloxyolean-12-en-24(4β)-oic acid methyl ester(Compound 72)

Compound 10 (15 mg) was dissolved in 1 ml of methanol, and a solution oftrimethylsilyldiazomethane in hexane was added to the solution untilyellow color became not disappeared. After the reaction mixture wasconcentrated under reduced pressure, the residue was purified by columnchromatography on silica gel (n-hexane:ethyl acetate=4:1) to give 13 mg(yield 83%) of compound 72 as a colorless foam substance.

NMR (CDCl₃) δ ppm 0.83 (3H, s), 0.89 (3H, s), 0.93 (3H, s), 0.95 (3H,s), 1.04 (3H, s), 1.09 (3H, s), 1.31 (3H, s), 0.85-2.32 (21H, m), 2.96(1H, dd, J=4.16 Hz, 11.93 Hz), 3.07 (1H, dd, J=3.05 Hz, 6.38 Hz), 3.65(3H, s), 4.32 (1H, d, J=11.93 Hz), 4.48 (1H, d, J=12.21 Hz), 4.61 (1H,d, J=11.93 Hz), 4.72 (1H, d, J=12.21 Hz), 5.22 (1H, t-like), 7.26-7.37(10H, m).

MS FAB (m/z): 667 (M⁺+l)

Example 65 3β,22β-Dihydroxyolean-12-en-24(4β)-oic acid methyl ester(Compound 73)

The procedure of Example 8 was repeated, except that 12 mg of compound72 was used as the starting compound. Thus, 9 mg (yield 100%) ofcompound 73 was prepared as a colorless solid.

NMR (CDCl₃) δ ppm 0.80 (3H, s), 0.88 (3H, s), 0.92 (3H, s), 0.99 (3H,s), 1.04 (3H, s), 1.12 (3H, s), 1.42 (3H, s), 0.72-2.12 (21H, m),3.07-3.13 (1H, m), 3.43-3.48 (1H, m), 3.69 (3H, s), 5.27 (1H, t-like).

MS EI (m/z): 486 (M⁺)

The substituents in the formula (I-1) corresponding to the structures ofthe compounds 1 to 73 are as shown in Table 1.

TABLE 1 COMPOUND NO. R¹ R² R³(α) R⁴(β) 1 —OC(CH₃)₂OCH₂— H OH 2 OH CH₂OH═O 3 OH CH₂OH Me OH 4 OH CH₂OTr H OH 5 OBn CH₂OTr H OBn 6 OBn CH₂OH HOBn 7 OBn CHO H OBn 8 OH CHO H OH 9 OH CH₂OH H OH 10 OBn COOH H OBn 11OH COOH H OH 12 OH CH₂OH ═CH₂ 13 OH CH₂OH Me H 14 OH CH₂OH H CH₂OH 15—OC(CH₃)₂OCH₂— H CH₂OH 16 —OC(CH₃)₂OCH₂— H CHO 17 OH CH₂OH H CHO 18—OC(CH₃)₂OCH₂— H COOH 19 OH CH₂OH H COOH 20 —OC(CH₃)₂OCH₂— H OTs 21—OC(CH₃)₂OCH₂— H — 22 OH CH₂OH H — 23 OH CH₂OH H H 24 —OC(CH₃)₂OCH₂— HOAc 25 OH CH₂OH H OAc 26 —OC(CH₃)₂OCH₂— H OMe 27 OH CH₂OH H OMe 28 OH MeH OH 29 OMe CH₂OMe H OMe 30 —OC(CH₃)₂OCH₂— H OBn 31 OH CH₂OH H OBn 32—OC(CH₃)₂CH₂— H OEt 33 OH CH₂OH H OEt 34 —OC(CH₃)₂CH₂— H OCH₂CH═CH₂ 35OH CH₂OH H OCH₂CH═CH₂ 36 —OC(CH₃)₂OCH₂— H OCCPh 37 OH CH₂OH H OCCPh 38—OC(CH₃)₂OCH₂— H OCOEt 39 OH CH₂OH H OCOEt 40 —OC(CH₃)₂OCH₂— H OCO^(n)Bu41 OH CH₂OH H OCO^(n)Bu 42 —OC(CH₃)₂OCH₂— H OCOCH═CHCH₃ 43 OH CH₂OH HOCOCH═CHCH₃ 44 —OC(CH₃)₂OCH₂— H OCOCH—CHPh 45 OH CH₂OH H OCOCH—CHPh 46OBn CH₂NHCH₃ H OBn 47 OH CH₂NHCH₃ H OH 48 —OCH(Ph)OCH₂— H H 49 OBn CH₂OHH H 50 OH CH₂OBn H H 51 OBn CH₂OAc H H 52 OH CH₂OAc H H 53 OBn CH₂OMe HH 54 OH CH₂OMe H H 55 OAc CH₂OBn H H 56 OAc OH₂OH H H 57 OCH₃ CH₂OBn H H58 OCH₃ CH₂OH H H 59 OBn CH₂OAc H OBn 60 OH CH₂OAc H OH 61 OBn CH₂OCOEtH OBn 62 OH CH₂OCOEt H OH 63 OBn CH₂OMe H OBn 64 OH CH₂OMe H OH 65—OCH(Ph)OCH₂— H OH 66 —OCH(Ph)OCH₂— H OBn 67 OH CH₂OBn H OBn 68 OAcCH₂OBn H OBn 69 OAc CH₂OH H OH 70 OCH₃ CH₂OBn H OBn 71 OCH₃ CH₂OH H OH72 OBn COOMe H OBn 73 OH COOMe H OH

In the table,

Tr represents a trityl group, Bn a benzyl group, and Ts a tosyl group.

In the the compounds 1 to 20 and 23 to 73, — — — represents a singlebond. On the other hand, in the compounds 21 and 22, — — — represents adouble bond.

PREPARATION EXAMPLE 1

Tablets

The compound of the present invention was granulated by the wet process.After magnesium stearate was added thereto, the mixture was compressedto prepare tablets. Each tablet had the following composition.

Compound 9 200 mg Lactose 50 mg Carboxymethyl starch sodium 20 mgHydroxypropylmethyl cellulose 5 mg Magnesium stearate 3 mg Total 278 mg

PREPARATION EXAMPLE 2

Suppositories

Weilapzole H-15 was heated at 60° C., and the compound 9 was added toand dispersed in the resultant melt. The dispersion was filled intosuppository containers. The suppository containers were then cooled toroom temperature to prepare suppositories. Each suppository had thefollowing composition.

Compound 9 200 mg Weilapzole H-15 1000 mg Total 1200 mg

TEST EXAMPLE 1

Study With Hepatocytotoxicity Inhibitory Model (In Vitro)

A test compound was added to a concentration of 0.1 to 10 μg/ml to HepG2 cells in the presence of aflatoxin B₁ (10⁻⁵ M). The cells were thenincubated in a CO₂ incubator at 37° C. for 48 hr. After the incubation,the cells were dyed with trypan blue. The dye incorporation capacitythereof was measured with Monocellater (manufactured by Olympus OpticalCo., Ltd.). The hepatocytotoxicity inhibitory activity (%) wascalculated according to the following equation. In the equation, thevalue of the control group is the absorbance (%) in the presence ofaflatoxin B₁ alone, and the value of the treated group is the absorbance(%) in the copresence of aflatoxin B₁ and the test compound.

As a result, the hepatocytotoxicity inhibitory activity of the compounds1, 3, 8, 9, 10, 11, 14, 19, 23, 25, 27, 35, 37, 43, 45, 52, 54, 60, 64,71, and 73 was more than 5%. $\begin{matrix}{Hepatocytotoxicity} \\{{inhibitory}\quad {activity}\quad (\%)}\end{matrix} = {\frac{\begin{matrix}{{value}\quad {of}} \\{{control}\quad {group}}\end{matrix} - \begin{matrix}{{value}\quad {of}} \\{{treated}\quad {group}}\end{matrix}}{100 - {{value}\quad {of}\quad {control}\quad {group}}} \times 100}$

Acute Toxicity

The compound 9 of the present invention was intravenously administeredto a C3H male mouse at a dose of 4 mg/kg, twice a day for 3 days. As aresult, there is no significant toxicity.

What is claimed is:
 1. A triterpene derivative represented by theformula (II) or a pharmaceutically acceptable salt thereof:

wherein R¹ represents a hydroxyl group, C₁₋₆ alkoxy, C₁₋₆alkylcarbonyloxy, or aralkyloxy which may be optionally substituted; R²represents C₁₋₆ alkyl, —CH₂OR⁵ wherein R⁵ represents a hydrogen atom,C₁₋₆ alkyl, aralkyl which may be optionally substituted, or C₁₋₆alkylcarbonyl, formyl, —COOR⁶ wherein R⁶ represents a hydrogen atom orC₁₋₆ alkyl), or —CH₂N(R⁷)R⁸ wherein R⁷ and R⁸, which may be the same ordifferent, represent a hydrogen atom or C₁₋₆ alkyl; or R¹ and R² maycombine with each other to form —O—CR⁹(R¹⁰)—OCH₂— wherein R⁹ and R¹⁰,which may be the same or different, represent a hydrogen atom, a C₁₋₆alkyl group, or an aryl group; R³ and R⁴, which may be the same ordifferent, represent C₁₋₆ alkyl, hydroxy C₁₋₆ alkyl, formyl, —COOR¹¹wherein R¹¹ represents a hydrogen atom or C₁₋₆ alkyl, or —OR¹² whereinR¹² represents C₁₋₆ alkyl, aralkyl which may be optionally substituted,arylcarbonyl, C₂₋₆ alkenyl, C₂₋₆ alkenylcarbonyl, or arylalkenylcarbonylwhich may be optionally substituted; or R³ and R⁴ may combine with eachother to form a methylene group; — — — represents a single or doublebond, provided that, when — — — represents a double bond, R⁴ is absent;when R¹ and R² combine with each other to form —O—CR⁹(R¹⁰)—OCH₂— whereinany one of R⁹ and R¹⁰ represents aryl, R³ and R⁴ may further represent ahydrogen atom or a hydroxyl group; when any one of R³ and R⁴ representsa C₁₋₆ alkyl group, the other substituent may further represent ahydroxyl group.
 2. The compound according to claim 1, wherein R¹represents a hydroxyl group and R² represents CH₂OR⁵.
 3. The compoundaccording to claim 2, wherein R⁵ represents a hydrogen atom and R⁴represents —OR¹² wherein R¹² represents C₁₋₆ alkyl, aralkyl which may beoptionally substituted, arylcarbonyl which may be optionallysubstituted, C₂₋₆ alkenyl, C₂₋₆ alkenylcarbonyl, or arylalkenylcarbonylwhich may be optionally substituted.
 4. The compound according to claim1, wherein R¹ and R² combine with each other to form —O—CR⁹(R¹⁰)—OCH₂.5. The compound according to claim 4, wherein R⁹ and R¹⁰ representmethyl, R³ represents a hydrogen atom and R⁴ represents —OR¹² whereinR¹² represents C₁₋₆ alkyl, arylcarbonyl which may be optionallysubstituted, C₂₋₆ alkenyl, C₂₋₆ alkenylcarbonyl, or arylalkenylcarbonylwhich may be optionally substituted.
 6. The compound according to claim4, wherein R⁹ represents a hydrogen atom and R¹⁰ represents aryl.
 7. Thecompound according to claim 6, wherein R³ and R⁴ represent a hydrogenatom.
 8. The compound according to claim 4, wherein R⁴ represents ahydroxyl group or aralkyloxy which may be optionally substituted.
 9. Thecompound according to claim 1, wherein R¹ represents a hydroxyl group,R² represents —CH₂OR⁵, R³ represents C₁₋₆ alkyl and R⁴ represents ahydroxyl group.
 10. The compound according to claim 9, wherein R⁵represents a hydrogen atom.
 11. A triterpene derivative represented bythe formula (II) or a pharmaceutically acceptable salt thereof:

wherein R¹ represents a hydroxyl group; R² represents —CH₂OR⁵ wherein R⁵represents a hydrogen atom, C₁₋₆ alkyl, aralkyl which may be optionallysubstituted, or C₁₋₆ alkylcarbonyl; R³ represents a hydrogen atom; andR⁴ represents C₁₋₆ alkyl, hydroxy C₁₋₆ alkyl, formyl, —COOR¹¹ whereinR¹¹ represents a hydrogen atom or C₁₋₆ alkyl, or —OR¹² wherein R¹²represents C₁₋₆ alkyl, aralkyl which may be optionally substituted,arylcarbonyl which may be optionally substituted, C₂₋₆ alkenyl, C₂₋₆alkenylcarbonyl, or arylalkenylcarbonyl which may be optionallysubstituted.
 12. The compound according to claim 11, wherein R⁵represents a hydrogen atom and R⁴ represents —OR¹² wherein R¹²represents C₁₋₆ alkyl, aralkyl which may be optionally substituted,arylcarbonyl which may be optionally substituted, C₂₋₆ alkeenyl, C₂₋₆alkenylcarbonyl, or arylalkenylcarbonyl which may be optionallysubstituted.
 13. The compound according to claim 11, wherein R¹represents a hydroxyl group, R² represents —CH₂OR⁵, R³ represents ahydrogen atom and R⁴ represents hydroxy C₁₋₆ alkyl or —COOR¹¹.
 14. Thecompound according to claim 13, wherein R⁵ represents a hydrogen atomand R¹¹ represents a hydrogen atom.
 15. A triterpene derivativerepresented by the formula (II) or a pharmaceutically acceptable saltthereof:

wherein R¹ represents aralkyloxy which may be optionally substituted, R²represents —CH₂OR⁵, wherein R⁵ represents a hydrogen atom, C₁₋₆ alkyl,or C₁₋₆ alkylcarbonyl, and R³ and R⁴ represent a hydrogen atom.
 16. Atriterpene derivative represented by the formula (II) or apharmaceutically acceptable salt thereof:

wherein R¹ represents a hydroxyl group, R² represents —CH₂OR⁵, whereinR⁵ represents C₁₋ ₆ alkyl or C₁₋ ₆ alkylcarbonyl, and R³ and R⁴represent a hydrogen atom.
 17. A triterpene derivative represented bythe formula (II) or a pharmaceutically acceptable salt thereof:

wherein R¹ represents a hydroxyl group, C₁₋₆ alkoxy, or C₁₋₆alkylcarbonyloxy, R² represents —CH₂OR⁵, wherein R⁵ represents aralkylwhich may be optionally substituted, and R³ and R⁴ represent a hydrogenatom.
 18. A triterpene derivative represented by the formula (II) or apharmaceutically acceptable salt thereof:

wherein R¹ represents C₁₋₆ alkoxy or C₁₋₆ alkylcarbonyloxy, R²represents —CH₂OH and R³ and R⁴ represent a hydrogen atom.
 19. Thecompound according to claim 1, wherein R¹ represents a hydroxyl group,R² represents —CH₂OR⁵ and R³ and R⁴ combine with each other to form amethylene group.
 20. The compound according to claim 19, wherein R⁵represents a hydrogen atom.
 21. The compound according to claim 1,wherein R¹ and R² combine with each other to form —O—CR⁹(R¹⁰)—OCH₂— and— — — represents a double bond.
 22. The compound according to claim 21,wherein R⁹ and R¹⁰ represent a methyl group.
 23. A triterpene derivativerepresented by the formula (II) or a pharmaceutically acceptable saltthereof:

wherein in the formula (II), R¹ represents a hydroxyl group, R²represents —COO—C₁₋₆ alkyl, R³ represents a hydrogen atom and R⁴represents a hydroxyl group.
 24. A triterpene derivative represented bythe formula (II) or a pharmaceutically acceptable salt thereof:

wherein in the formula (II), R¹ represents C₁₋₆ alkoxy, R² represents—CH₂OH, R³ represents a hydrogen atom and R⁴ represents a hydroxylgroup.
 25. A triterpene derivative represented by the formula (II) or apharmaceutically acceptable salt thereof:

wherein in the formula (II), R¹ represents aralkyloxy, R² representsformyl, carboxyl, —COO—C₁₋₆ alkyl or —CH₂OR⁵, wherein R⁵ represents ahydrogen atom, C₁₋₆ alkyl or C₁₋₆ alkylcarbonyl, R³ represents ahydrogen atom and R⁴ represents aralkyloxy.
 26. A triterpene derivativerepresented by the formula (II) or a pharmaceutically acceptable saltthereof:

wherein in the formula (II), R¹ represents a hydroxyl group or C₁₋₆alkoxy, R² represents aralkyloxymethyl, R³ represents a hydrogen atomand R⁴ represents aralkyloxy.
 27. The compound according to claim 1,which has a configuration represented by the following formula (II-1):


28. A method for treating a hepatic disorder excluding autoimmunehepatitis, comprising the step of administering to a mammal, including ahuman, a triterpene derivative represented by the formula (I) or apharmaceutically acceptable salt thereof:

wherein R¹ represents a hydroxyl group, C₁₋₆ alkoxy, C₁₋₆alkylcarbonyloxy, or aralkyloxy which may be optionally substituted; R²represents C₁₋₆ alkyl, —CH₂OR⁵ wherein R⁵ represents a hydrogen atom,C₁₋₆ alkyl, aralkyl which may be optionally substituted, or C₁₋₆alkylcarbonyl, formyl, —COOR⁶ wherein R⁶ represents a hydrogen atom orC₁₋₆ alkyl), or —CH₂N(R⁷)R⁸ wherein R⁷ and R⁸, which may be the same ordifferent, represent a hydrogen atom or C₁₋₆ alkyl; or R¹ and R² maycombine with each other to form —O—CR⁹(R¹⁰)—OCH₂— wherein R⁹ and R¹⁰,which may be the same or different, represent a hydrogen atom, C₁₋₆alkyl, or aryl which may be optionally substituted; R³ and R⁴, which maybe the same or different, represent a hydrogen atom, a hydroxyl group,C₁₋₆ alkyl, hydroxy C₁₋₆ alkyl, formyl, —COOR¹¹ wherein R¹¹ represents ahydrogen atom or C₁₋₆ alkyl, or —OR¹² wherein R¹² represents C₁₋₆ alkyl,aralkyl which may be optionally substituted, optionally substituted C₁₋₆alkylcarbonyl, arylcarbonyl, C₂₋₆ alkenyl, C₂₋₆ alkenylcarbonyl, orarylalkenylcarbonyl which may be optionally substituted; or R³ and R⁴combine with each other to form a methylene group =O; — — — represents asingle or double bond, provided that, when — — — represents a doublebond, R⁴ is absent.
 29. The method for treating a hepatic disorderaccording to claim 28, wherein R¹ represents a hydroxyl group, R²represents —CH₂OR⁵ and R³ represents a hydrogen atom.
 30. The method fortreating a hepatic disorder according to claim 29, wherein R⁴ representsa hydroxyl group or —OR¹².
 31. The method for treating a hepaticdisorder according to claim 28, wherein R¹ represents C₁₋₆ alkoxy. 32.The method for treating a hepatic disorder according to claim 28,wherein R¹ represents a hydroxyl group, R² represents formyl, R³represents a hydrogen atom and R⁴ represents a hydroxyl group.
 33. Themethod for treating a hepatic disorder according to claim 28, wherein R¹represents a hydroxyl group or aralkyloxy which may be optionallysubstituted, R² represents —COOR⁶, R³ represents a hydrogen atom and R⁴represents a hydroxyl group or —OR¹².
 34. The method for treating ahepatic disorder according to claim 28, wherein R¹ represents a hydroxylgroup, C₁₋₆ alkoxy, C₁₋₆ alkylcarbonyloxy, R² represents —CH₂OR⁵ and R³and R⁴ represent a hydrogen atom.
 35. The method for treating a hepaticdisorder according to claim 28, wherein R¹ represents a hydroxyl group,R² represents —CH₂OR⁵, R³ represents C₁₋₆ alkyl and R⁴ represents ahydroxyl group.
 36. The method for treating a hepatic disorder accordingto claim 28, wherein R¹ represents a hydroxyl group, R² represents—CH₂OR⁵, R³ represents a hydrogen atom and R⁴ represents hydroxy C₁₋₆alkyl or carboxyl.
 37. The method for treating a hepatic disorderaccording to claim 28, wherein the hepatic disorder is acute or chronicviral hepatitis, or drug-induced, toxic, alcoholic, intrahepaticcholestasis, or inborn metabolic error hepatopathy.
 38. The method fortreating a hepatic disorder according to claim 28, wherein thetriterpene derivative represented by the formula (I) has a configurationrepresented by the following formula (I-1):


39. A pharmaceutical composition comprising the triterpene derivative orthe pharmaceutically acceptable salt thereof according to claim
 1. 40.22β-Methoxyolean-12-ene-3β,24(4β)-diol or a pharmaceutically acceptablesalt thereof.
 41. 22β-Ethoxyolean-12-ene-3β,24(4β)-diol or apharmaceutically acceptable salt thereof.